Novel isocarbacyclins and processes for production thereof

ABSTRACT

A novel isocarbacyclin which is a compound represented by the following formula ##STR1## wherein R 1  represents a hydrogen atom, or a C 1  -C 4  alkyl or alkenyl group; R 2  and R 3  are identical or different and each represents a hydrogen atom, a tri(C 1  -C 7 )hydrocarbon-silyl group or a group forming an acetal linkage together with the oxygen atom of the hydroxyl group; R 4  represents a hydrogen atom, a methyl group or a vinyl group; R 5  represents an unsubstituted linear or branched C 3  -C 8  alkyl group which may be interrupted by an oxygen atom, a substituted linear or branched C 1  -C 5  group in which the substituent is a C 1  -C 6  alkoxy group or a phenyl, phenoxy or C 3  -C 10  cycloalkyl group which may be substituted further, a phenyl group which may be substituted, a phenoxy group which may be substituted, or a C 3  -C 10  cycloalkyl group which may be substituted; n is 0 or 1; and Ar represents a substituted or unsubstituted phenyl group, its enantiomorph, or a mixture both in an arbitrary ratio.

This invention relates to novel isocarbacyclins and processes forproduction thereof.

More specifically, this invention relates to novel isocarbacyclinederivatives which are intermediates for synthesis of 9(O)-methano-Δ⁶(9α)-prostaglandin I₁ (isocarbacyclin) resulting from substitution of amethine group (--HC═) for the oxygen atoms at the 6,9-positions ofprostaglandin I₁, and to processes for production thereof.

Prostaglandin is a local hormone produced mainly in the inner vascularwall of the artery in an animal. It is an important factor forcontrolling the cell functions of the living body by its strongphysiological activities such as platelet aggregation inhibitoryactivity and vasodilating activity. Attempts have been made to use itdirectly as a medicine (Clinical Pharmacology of Prostacyclin, RavenPress, N.Y., 1981).

Natural prostacyclin readily loses activity under neutral or acidicconditions because it has a very hydrolyzable enol ether linkage in themolecule. It is therefore undesirable as a medicine because of itschemical instability. Thus, extensive investigations have been conductedworldwide on chemically stable synthetic prostacyclin derivatives havingthe same physiological activities as the natural prostacyclin.

A derivative derived by substituting a methylene group for the oxygenatoms at the 6,9-position of prostacyclin, i.e. 9(O)-methanoprostacyclin(cabacyclin), is known to have fully satisfactory chemical stability(Prostacyclin, J. R. Vane and S. Bergstrom, Eds., Raven Press, N.Y., pp.31-4). It is expected to be used as a medicine. However, 6,9(O)-methanoprostacyclin is not entirely desirable because its biologicalactivities are weaker than those of natural prostacyclin and theselectivity of its action is not specific.

It was recently discovered that isocarbacyclins, i.e.9(O)-methano-Δ⁶(9α) -prostaglandins I₁, which are a kind of double bondisomers of carbacyclin, show the strongest platelet aggregationinhibiting activity among the prostacyclin analogs, and they areexpected to be applied as medicines [Ikegami et al., Tetahedron Letters,24, 3493 (1983), and Japanese Laid-Open Patent Publication No.137445/1984].

The following methods have previously been known for the production of9(O)-methano-Δ⁶(9α) -prostaglandin I₁ (isocarbacyclin).

(1) Ikegami et al., Tetrahedron Letters, 24, 3493 (1983) and ChemistryLetters, 1984, 1069: ##STR2##

(2) Ikegami et al., Tetrahedron Letters, 24, 3497 (1983): ##STR3##

(3) Ikegami et al., J. Chem. Soc., Chemical Communications, 1984, 1602:##STR4##

(4) Shibasaki et al., Tetrahedron Letters, 25, 5087 (1984): ##STR5##

(5) Shibasaki et al., Tetrahedron Letters, 25, 1067 (1984): ##STR6##

(6) Kojima et al., Chem. Pharm. Bull., 32, 2866 (1984): ##STR7##

(7) Kojima et al., Japanese Laid-Open Patent Publication No. 28943/1985:##STR8##

Among these seven methods, methods (1) and (5) cannot be said to beindustrially feasible since they start from PGE₂, require several stepsto convert it to a key intermediate and further require several steps toobtain the desired isocarbacyclin.

Methods (2) and (3) require many steps to obtain the correspondingstarting materials and key intermediates from expensive Corey's lactone,and the overall yield of the final product is not high. Hence, thesemethods are not entirely advantageous for industrial practice.

Methods (6) and (7) give the final products only in DL-form, and are notdesirable for giving products intended for pharmaceutical application.

In method (4), the starting material can be easily obtained fromoptically active (R)-4-hydroxy-2-cyclopentenone by the method of thepresent inventors (Japanese Laid-Open Patent Publication No.155116/1982), and the conversion of the starting material into a keyintermediate can be carried out without any problem in industrialpractice. This method, however, encounters various difficulties in itsroute from the key intermediate to the final isocarbacyclin, and is notindustrially feasible. For example, the use of an organic mercurycompound is necessary, or the regio specificity is lost. Moreover, sincean inseparable by-product occurs, the total yield of the final productis low.

In an attempt to overcome these difficulties, the present inventors havemade extensive investigations on 9(O)-methano-Δ⁶(9α) -prostaglandins I₁(isocarbacyclins) and a process for production thereof. Theseinvestigations have now led to the present invention.

According to this invention, there are provided a compound representedby the following formula [I] ##STR9## wherein R¹ represents a hydrogenatom, or a C₁ -C₄ alkyl or alkenyl group; R² and R³ are identical ordifferent and each represents a hydrogen atom, a tri(C₁-C₇)hydrocarbon-silyl group or a group forming an acetal linkagetogether with the oxygen atom of the hydroxyl group; R₄ represents ahydrogen atom, a methyl group or a vinyl group; R⁵ represents anunsubstituted linear or branched C₃ -C₈ alkyl group which may beinterrupted by an oxygen atom, a substituted linear or branched C₁ -C₅alkyl group in which the substituent is a C₁ -C₆ alkoxy group or aphenyl, phenoxy or C₃ -C₁₀ cycloalkyl group which may be substitutedfurther, a phenyl group which may be substituted, a phenoxy group whichmay be substituted, or a C₃ -C₁₀ cycloalkyl group which may besubstituted; n is 0 or 1; and Ar represents a substituted orunsubstituted phenyl group,

its enantiomorphs, or a mixture said compound and its enantiomorph in anarbitrary ratio; and processes for production thereof.

In formula [I], R¹ represents a hydrogen atom or an alkyl or alkenylgroup having 1 to 4 carbon atoms. Examples of the C₁ -C₄ alkyl group aremethyl, ethyl, propyl and butyl groups. Examples of the C₁ -C₄ alkenylgroup are 2-propene and 3-butene groups. Among these, methyl and2-propene groups are preferred.

In formula [I], R² and R³ are identical or different, and eachrepresents a hydrogen atom, a tri(C₁ -C₇)hydrocarbon-silyl group, or agroup forming an acetal linkage together with the oxygen atom of thehydroxyl group.

Examples of the tri(C₁ -C₇)hydrocarbon-silyl group include tri(C₁-C₄)alkylsilyl groups such as trimethylsilyl, triethylsilyl,triisopropylsilyl and t-butyldimethylsilyl groups, diphenyl(C₁-C₄)alkylsilyl groups such as a t-butyldiphenylsilyl group, di(C₁-C₄)alkylphenylsilyl groups such as a dimethylphenylsilyl group, and atribenzylsilyl group. Of these, the tri(C₁ -C₄)alkylsilyl groups,diphenyl(C₁ -C₄)alkylsilyl groups, and phenyldi(C₁ -C₄)alkylsilyl groupsare preferred, and t-butyldimethylsilyl and trimethylsilyl groups areespecially preferred.

Examples of the group forming an acetal linkage together with the oxygenatom of the hydroxyl group include methoxymethyl, 1-ethoxyethyl,2-methoxy-2-propyl, 2-ethoxy-2-propyl, (2-methoxyethoxy)methyl,benzyloxymethyl, 2-tetrahydropyranyl, 2-tetrahydrofuranyl and6,6-dimethyl-3-oxa-2-oxobicyclo[3.1.0]hex-4-yl groups. The2-tetrahydropyranyl, 2-tetrahydrofuranyl, 1-ethoxyethyl,2-ethoxy-2-propyl, (2-methoxyethoxy)methyl and6,6-dimethyl-3-oxa-2-oxobicyclo[3.1.0]hex-4-yl groups are especiallypreferred. Above all, 2-tetrahydropyranyl is most preferred.

It should be understood that the silyl groups and the groups forming anacetal linkage are protective groups for the hydroxyl group. Theseprotective groups can be easily removed under weakly acidic to neutralconditions in the stage of the final product to give a free hydroxylgroup useful for drugs.

In formula [I], R⁴ represents a hydrogen atom, a methyl group, and avinyl group.

In formula [I], R⁵ represents an unsubstituted linear or branched C₃ -C₈alkyl group which may be interrupted by an oxygen atom, a substitutedlinear or branched C₁ -C₅ alkyl group in which the substituent is a C₁-C₆ alkoxy group or a phenyl, phenoxy or C₃ -C₁₀ cycloalkyl group whichmay be substituted further, a phenyl group which may be substituted, aphenoxy group which may be substituted, or a C₃ -C₁₀ cycloalkyl groupwhich may be substituted.

Preferred examples of the unsubstituted linear or branched C₃ -C₈ alkylgroup which may be interrupted by an oxygen atom include propyl, butyl,pentyl, hexyl, heptyl, 2-hexyl, 2-methyl-2-hexyl, 2-methylbutyl,2-methylpentyl, 2-methylhexyl and 2,2-dimethylhexyl.

Examples of the substituents in the substituted phenyl, phenoxy and C₃-C₁₀ cycloalkyl groups include halogen atoms, protected hydroxyl groups(such as silyloxy and C₁ -C₈ alkoxy groups), and C₁ -C₄ alkyl groups.Illustrative of the C₃ -C₁₀ cycloalkyl groups are cyclopropyl,cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, andcyclodecyl groups. Of these, cyclopentyl and cyclohexyl groups arepreferred.

In the linear or branched C₁ -C₅ alkyl group substituted by a C₁ -C₆alkoxy or a phenyl, phenoxy or C₃ -C₁₀ cycloalkyl which may besubstituted, examples of the C₁ -C₆ alkoxy group include methoxy,ethoxy, propoxy, isopropoxy, butoxy, t-butoxy and hexyloxy groups. Thesubstituents of the phenyl, phenoxy or C₃ -C₁₀ cycloalkyl group whichmay be substituted, and the C₃ -C₁₀ cycloalkyl group may be the same asexemplified hereinabove. Examples of the linear or branched C₁ -C₅ alkylgroups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,t-butyl and pentyl groups. Preferred examples of R⁵ are butyl, pentyl,hexyl, heptyl, 2-hexyl, 2-methyl-2-hexyl, 2-methylbutyl, 2-methylpentyl,cyclopentyl, cyclohexyl, phenyl, phenoxy, cyclopentylmethyl andcyclohexylmethyl groups. The substituents may be attached to arbitrarypositions.

In formula [I], n represents 0 or 1, and Ar represents a substituted orunsubstituted phenyl group. Examples of the substituent for phenyl arephenyl and p-tolyl groups.

The compounds of formula [I] include stereoisomers since the bridgeheadcarbon atoms (1- and 5-positions) and the carbon atom which issubstituted by OR² or ω-side chain (6- and 7-positions) of thebicyclo[3.3.0]octene ring, and the carbon atom which is substituted byOR³ of ω-side chain are asymmetric. The compounds of this inventioninclude any of these stereoisomers, and mixtures thereof in arbitraryratios. Of these, compounds having a steric structure expressed by theformula are most preferred.

Specific preferred examples of the 3,6,7-trisubstitutedbicyclo[3.3.0]-2-octenes of formula [I] provided by this invention areshown below.

(1) (1S, 5S, 6S,7R)-3-(4-carbomethoxy-2,2-bisphenylsulfonylbutyl)-6-[(E,3S)-3-hydroxy-1-octenyl]-7-hydroxybicyclo[3.3.0]-2-octene

(2) (1S, 5S, 6S,7R)-3-(4-carbomethoxy-2,2-bisphenylsulfonylbutyl)-6-[(E,3S)-3-hydroxy-1-nonenyl]-7-hydroxybicyclo[3.3.0]-2-octene

(3) (1S, 5S, 6S,7R)-3-(4-carbomethoxy-2,2-bisphenylsulfonylbutyl)-6-[(E,3S)-3-hydroxy-4-methyl-1-octenyl]-7-hydroxybicyclo[3.3.0]-2-octene

(4) (1S, 5S, 6S,7R)-3-(4-carbomethoxy-2,2-bisphenylsulfonylbutyl)-6-[(E,3S)-3-hydroxy-4,4-dimethyl-1-octenyl]-7-hydroxybicyclo[3.3.0]-2-octene

(5) 1S, 5S, 6S, 7R)-3-(4-carbomethoxy-2,2-bisphenylsulfonylbutyl)-6-[(E,3S)-3-hydroxy-5-methyl-1-octenyl]-7-hydroxybicyclo[3.3.0]-2-octene

(6) (1S, 5S, 6S,7R)-3-(4-carbomethoxy-2,2-bisphenylsulfonylbutyl)-6-[(E,3S)-3-hydroxy-5-methyl-1-nonenyl]-7-hydroxybicyclo[3.3.0]-2-octene

(7) 6-[(E, 3S, 5S) . . . ] form of (6)

(8) 6-[(E, 3S, 5S) . . . ] form of (6)

(9) (1S, 5S, 6S,7R)-3-(4-carbomethoxy-2,2-bisphenylsulfonylbutyl)-6-[(E,3S)-3-hydroxy-3-cyclopentyl-1-propenyl]-7-hydroxybicyclo[3.3.0]-2-octene

(10) (1S, 5S, 6S,7R)-3-(4-carbomethoxy-2,2-bisphenylsulfonylbutyl)-6-[(E,3S)-3-hydroxy-3-cyclohexyl-1-propenyl]-7-hydroxybicyclo[3.3.0]-2-octene

(11) (1S, 5S, 6S,7R)-3-(4-carbomethoxy-2,2-bisphenylsulfonylbutyl)-6-[(E,3S)-3-hydroxy-3-cyclohexyl-1-butenyl]-7-hydroxybicyclo[3.3.0]-2-octene

(12) (1S, 5S, 6S,7R)-3-(4-carbomethoxy-2,2-bisphenylsulfonylbutyl)-6-[(E,3S)-3-hydroxy-5-phenoxy-1-pentenyl]-7-hydroxybicyclo[3.3.0]-2-octene

(13) (1S, 5S, 6S,7R)-3-(4-carbomethoxy-2,2-bisphenylsulfonylbutyl)-6-[(E,3S)-3-hydroxy-5-ethoxy-1-pentenyl]-7-hydroxybicyclo[3.3.0]-2-octene

(14) (1S, 5S, 6S,7R)-3-(4-carbomethoxy-2,2-bisphenylsulfonylbutyl)-6-[(E,4S)-4-hydroxy-4-methyl-1-octenyl]-7-hydroxybicyclo[3.3.0]-2-octene

(15) (1S, 5S, 6S,7R)-3-(4-carbomethoxy-2,2-bisphenylsulfonylbutyl)-6-[(E,4R)-4-hydroxy-4-methyl-1-octenyl]-7-hydroxybicyclo[3.3.0]-2-octene

(16) (1S, 5S, 6S,7R)-3-(4-carbomethoxy-2,2-bisphenylsulfonylbutyl)-6-[(E)-4-hydroxy-4-vinyl-1-octenyl]-7-hydroxybicyclo[3.3.0]-2-octene

(17) (1S, 5S, 6S,7R)-3-(4-carbomethoxy-2,2-bisphenylsulfonylbutyl)-6-[(E)-3-hydroxy-1-hept-7-en-1-yl]-7-hydroxybicyclo[3.3.0]-2-octene

(18) (1S, 5S, 6S,7R)-3-(4-carbomethoxy-2,2-bisphenylsulfonylbutyl)-6-[(+)-3-hydroxy-1-oct-6-en-1-yl]-7-hydroxybicyclo[3.3.0]-2-octene

(19) 3-(4-carbomethoxy-1-p-trisulfonylbutyl) forms of (1) to (18)

(20) Compounds corresponding to (1) to (9) in which the methyl ester isa carboxylic acid

(21) Compounds corresponding to (1) to (9) in which the methyl esterchanged to an allyl ester

(22) Compounds corresponding to (1) to (21) in which the hydroxyl groupat the 7-position and the hydroxyl group on the substituent at the6-position are protected with t-butyldimethylsilyl groups

(23) Compounds corresponding to (1) to (21) in which the hydroxyl groupson the substituents on the 7- and 6-positions are protected with2-tetrahydropyranyl groups

(24) Enantiomorphs of compounds (1) to (23)

(25) Stereoisomers at the asymmetric carbons at which the hydroxylgroups on the substituents at the 1-, 5-, 6-, 7- and 6-positions of thecompounds (1) to (23) are substituted

The novel isocarbacyclins of formula [I] can be produced by treating acompound represented by the following formula [II] ##STR10## wherein R¹¹represents a C₁ -C₄ alkyl or alkenyl group, and Ar is as defined above,with a base, thereafter reacting the teated product regio-specificallywith a 3,6,7-trisubstituted bicyclo[3.3.0]-2-octene which is a compoundrepresented by the following formula [III-a] ##STR11## wherein R²¹ andR³¹ are identical or different and each represents a tri(C₁-C₇)hydrocarbonsilyl group or a group forming an acetal linkage togetherwith the oxygen atom of the hydroxyl group, R⁶ represents a C₁ -C₆hydrocarbon group, and R⁴, R⁵ and n are as defined above, or itsenantiomorph, or a mixture of both in an arbitrary ratio, in thepresence of a palladium compound, and as required, subjecting theresulting product to a deprotection reaction or a hydrolysis reaction.

Likewise, the novel isocarbacyclins of formula [I] can be produced bytreating a compound represented by the following formula [II] ##STR12##wherein R¹¹ and Ar are as defined above, with a base, thereafterreacting the teated product regio-specifically with a3-methylene-2,6,7-trisubstituted bicyclo[3.3.0]-octene which is acompound represented by the following formula [IV-a] ##STR13## whereinR²¹, R³¹, R⁴, R⁵, R⁶ and n are as defined above, its enantiomorph, or amixture of both in an arbitrary ratio, in the presence of a palladiumcompound, and as required, subjecting the resulting product todeprotecting reaction or hydrolysis reaction.

The isocarbacyclins of formula [I] can also be produced by reacting a3,6,7-trisubstituted bicyclo[3.3.0]-2-octene which is a compoundrepresented by the folowing formula [III-b] ##STR14## wherein R⁷represents a C₁ -C₄ alkyl group, and R⁴, R⁵, R²¹, R³¹ and n are asdefined above, its enantiomorph, or a mixture of both in an arbitraryratio regio-specifically with a compound represented by the followingformula [II] ##STR15## wherein Ar and R¹¹ are as defined above, in thepresence of a palladium compound, and as required, subjecting theresulting product to deprotecting reaction or hydrolysis reaction.

The isocarbocyclins of formula [I] can further be produced by reacting a3-methylene-2,6,7-trisubstituted bicyclo[3.3.0]-octane which is acompound represented by the following formula [IV-b] ##STR16## whereinR⁴, R⁵, R⁷, R²¹, R³¹ and n are as defined above, its enantiomorph or amixture of both in an arbitrary ratio regio-specifically with acompounds of formula [II] given above in the presence of a palladiumcompound, and as required, subjecting the resulting product todeprotecting reaction and hydrolysis reaction.

In the starting bisarylsulfonyl compound of formula [II], R¹¹ representsan alkyl or alkenyl group having 1 to 4 carbon atoms. Preferred examplesof such groups are the same as those given hereinabove with regard to R¹in formula [I]. Especially preferably, R¹¹ is a methyl group.

In formula [II], Ar represents a substituted or unsubstituted phenylgroup which may be the same as exemplified with regard to Ar in formula[I]. Ar preferably represents a phenyl or p-tolyl group.

In the allylacyloxy compound of formula [III-a] or [IV-a] and thecarbonate compound of formula [III-b] or [IV-b], i.e. the other startingmaterials used in this invention, R²¹ and R³¹ are identical or differentand each represents a tri(C₁ -C₇)hydrocarbon-silyl or a group forming anacetal linkage together with the oxygen atom of the hydroxyl group.Preferred examples of the tri(C₁ -C₇)hydrocarbon-silyl group and theacetal forming group for R²¹ and R³¹ may be the same as exemplifiedhereinabove with regard to R² and R³ in formula [I].

In formulae [III-a], [IV-a], [III-b] and [IV-b], R⁴ represents ahydrogen atom, a methyl group or a vinyl group. R⁵ represents a linearor branched C₃ -C₉ alkyl group which may be interrupted by an oxygenatom; a substituted or unsubstituted phenyl group; a substituted orunsubstituted phenoxy group; a substituted or unsubstituted C₃ -C₁₀cycloalkyl group; or a linear or branched C₁ -C₅ alkyl group which issubstituted by a C₁ -C₈ alkoxy group, a phenyl group which may besubstituted, or a C₃ -C₁₀ cycloalkyl group which may be substituted.Preferred examples of R⁵ may be those exemplified hereinabove withregard to R⁵ in formula [I].

R⁶ in formula [III-a] or [IV-a] represents a hydrocarbon group having 1to 6 carbon atoms, and may includes methyl, ethyl, n-propyl, isopropyl,butyl and pentyl groups. The methyl group is preferred. R⁷ in formula[III-b] or [IV-b] represents a hydrocarbon group having 1 to 4 carbonatoms, and may include, for example, a methyl, ethyl, n-propyl,isopropyl or butyl group. The methyl group is preferred.

The 3,6,7-trisubstituted-bicyclo[3.3.0]-2-octenes represented byformulae [III-a] and [III-b] are produced by a method identical with, orsimilar to, the method described in Shibasaki et al., TetrahedronLetters, 25, 5087 (1984), which is schematically shown below in asimplified manner. ##STR17##

The 3-methylene-2,5,7-trisubstituted-bicyclo[3.3.0]-octanes representedby formulae [IV-a] and [IV-b] can be produced, for example, by a knownsynthesis route (route A shown below) from a6,7-disubstituted-3-hydroxymethylbicyclo[3.3.0]-2-octene produced by themethod described in the above-cited Tetrahedron Letters, 25, 5087 (1084)or a method similar to it. They can also be obtained by cyclization(route B) of an acetylene derivative obtained from the optically active4-hydroxy-2-cyclopentenone shown in the present invention. Thesereaction routes are briefly shown below. ##STR18##

The acylation reaction in the final step is carried out by reacting anacid chloride such as R⁶ COCl where R⁶ is as defined or an acidanhydride such as (R⁶ CO)₂ O with the allyl alcohol compound in thepresence of a base. On the other hand, the reaction of forming acarbonate compound is carried out by reacting a chloroformate derivativesuch as ClCOOR⁷ where R⁷ is as defined above with the allyl alcoholcompound in the presence of a base. Organic bases such as pyridine,triethylamine and diisopropylethylamine are preferably used as the base.As a result, the acyloxy compound of formula [III-a] or [IV-a] or thecarbonate compound of formula [III-b] or [IV-b] can be obtained.

Synthesis of the 4,4-bisarylsulfonylisocarbacyclin of formula [I] fromthe acyloxy compound of formula [III-a] or [IV-a] is carried out bytreating the bisarylsulfonyl compound of formula [II] with a base, andreacting the treated product with the acyloxy compound of formula[III-a] or [IV-a].

The bisaryl sulfonyl compound of formula [II] is used in an amount of0.9 to 30 equivalents, preferably 1 to 5 equivalents, based on theacyloxy compound of formula [III-a] or [IV-a]. Examples of the base totreat the bisaryl sulfonyl compound include organic alkali metalcompounds and alkali metal hydrides, such as n-butyllithium,sec-butyllithium, t-butyllithium, phenyllithium, methyllithium,naphthyllithium, trityllithium, lithium hydride, sodium hydroxide,potassium hydride, sodium methoxide and sodium ethoxide. Sodium hydrideis preferred. The amount of the base is 0.5 to 30 equivalents,preferably 1 to 10 equivalents, per equivalent of the bisarylsulfonylcompound of formula [II]. In principle, the amount of the base is oneequivalent. The temperature required for this salt-forming reaction is-100° C. to 100° C., preferably -78° C. to 2° C. The reaction time is 5minutes to 50 hours, preferably 10 minutes to 2 hours. The reaction iscarried out in an organic solvent, for example ethers such as diethylether, tetrahydrofuran and dioxane, hydrocarbons such as n-hexane andbenzene, dimethylformamide (DMF) and dimethyl sulfoxide (DMSO).Tetrahydrofuran is preferably used.

The resulting reaction mixture can be reacted with the allylacyloxycompound of formula [III-a] or [IV-a] without isolating the alkali metalsalt of the bisarylsulfonyl compound. This reaction is carried out inthe presence of palladium. For example, the various palladium complexesdescribed, for example, in Tetrahedron Letter, vol. 42, No. 16, pp.4361-4401, 1986, Accounts of Chemical Research, vol. 13, No. 11, pp.385-393, 1980, and J. Tsuji, "Organic Synthesis with PalladiumCompounds", Springer-Verlag (1980). Especially preferably,tetrakis[triphenylphosphine)palladium(O),bis[bis(1,2-diphenylphosphino)ethane]palladium(O), orbis[bis(1,3-diphenylphosphino)propane]palladium(O) is used.

Synthesis of the 4,4-bisarylsulfonyl isocarbacyclins of formula [I] fromthe carbonate compound of formula [III-b] or [IV-b] is carried out byreacting the bisarylsulfonyl compound of formula [II] with the carbonateof formula [III-b] or [IV-b] in the presence of palladium. Thebisarylsulfonyl compound of formula [II] is used in an amount of 0.5 to30 equivalents, preferably 1 to 5 equivalents, per equivalent of thecarbonate of formula [III-b] or [IV-b]. This reaction is carried out inthe presence of a palladium complex. The palladium compound ispreferably the one exemplified above. The amount of the palladiumcompound is 0.001 to 1 equivalent, preferably 0.01 to 0.2 equivalent,per equivalent of the carbonate of formula [III-b] or [IV-b]. Thereaction temperature is -30° C. to 200° C., preferably 0° to 100° C. Thereaction time is 10 minutes to 100 hours, preferably 0.5 to 24 hours. Asa reaction solvent, there may be used, for example, an ether such asdiethyl ether, tetrahydrofuran or dioxane, a hydrocarbon solvent such asn-hexane or benzene, DMF and DMSO. Tetrahydrofuran is preferred.

The reaction carried out by using the carbonate of formula [III-b] or[IV-b] has the following advantages.

(1) Since decarboxylation reaction by Pd(O) takes place, the reactionproceeds irreversibly and mild reaction conditions can be used.

(2) An alkyloxy anion (for example, MeO.sup.⊖) occurs as a result ofdecarboxylation and extracts the hydrogens ofmethyl-4,4'-bisphenylsulfonyl butanoate to generate a compound of thefollowing formula. ##STR19## Hence, without adding a base (such as NaH)in advance to the reaction system, the reaction proceeds.

The resulting reaction mixture is worked up by methods usuallypracticed. For example, a difficultly water-soluble organic solvent suchas hexane, pentane, diethyl ether or ethyl acetate is added to thereaction mixture. As required, the resulting mixture is washed with, forexample, aqueous sodium chloride solution, followed by drying over adesiccant such as anhydrous magnesium sulfate or anhydrous sodiumsulfate. Then, the organic solvent is removed under reduced pressure toobtain a crude product. As desired, the crude product can be purified bypurifying means such as column chromatography, thin-layer chromatographyor liquid chromatography.

When the resulting product is, as required, subjected to deprotectionreaction and hydrolysis, the reaction proceeds regio-specifically, andthe novel isocarbacyclin of formula [I] can be finally obtained. Theprotective group for the hydroxyl group can be carried out, for example,by treating the protected compound usually at a temperature of -78° C.to +30° C. using acetic acid, p-toluenesulfonic acid pyridinium salt ora cation exchange resin as a catalyst and water, tetrahydrofuran,diethyl ether, dioxane, acetone, acetonitrile, etc. as a reactionsolvent, if the protective group forms an acetal linkage together withthe oxygen atom of the hydroxyl group. If the protective group is atri(C₁ -C₇)hydrocarbon-silyl group, it is removed by treating theprotected compound in the same reaction solvent as above at the sametemperature in the presence of, for example, acetic acid, tetrabutylammonium fluoride, cerium fluoride, aqueous hydrogen fluoride solution,or pyridine-hydrogen fluoride.

Hydrolysis of the ester is carried out by an ordinary method, namely byreacting it in water or a water-containing solvent together with lithiumhydroxide, sodium hydroxide or potassium hydroxide at a temperature of-40° C. to +100° C., preferably 0° to 50° C., for 10 minutes to 24hours.

As a result, the compound of formula [I] having an isocarbacyclinskeleton is produced.

Route B shown hereinabove as a process for producing the3-methylene-2,6,7-trisubstituted-bicyclo[3.3.0]-octane of formula [IV-a]or [IV-b] is industrially important. The step of cyclizing the propargylcyclopentane and subsequent steps in the process, which are especiallyimportant, will be described below in detail.

The propargylcyclopentane which is a compound represented by thefollowing formula [V] ##STR20## wherein R²¹, R⁴, R⁵, R³¹ and n are asdefined above, its enantiomorph, or a mixture of both in an arbitraryratio is cyclized with a reducing agent containing a metal species, andas required, deprotected to give a6,7-disubstituted-2-hydroxy-3-methylenebicyclo[3.3.0]octane which is acompound represented by the following formula [VI] ##STR21## whereinR²¹, R⁴, R⁵, R³¹ and n are as defined above, its enantiomorph or amixture of both in an arbitrary ratio.

The metal species of the reducing agent used in the cyclization reactionmay, for example, be an alkali metal such as lithium, sodium andpotassium. Sodium and lithium are especially preferred. It may also bean alkaline earth metal such as calcium and magnesium. The amount of thealkali metal or the alkaline earth metal used is 1.0 to 20.0 moles,preferably 1.2 to 10.0 moles, per mole of the propargyl cyclopentane offormula [V].

The reducing agent such as the alkali metal or the alkaline earth metalis used as an anion radical solution in the cyclization reaction.Suitable solvents for the anion radical solution include liquid ammoniaand ether solvents such as diethyl ether, tetrahydrofuran anddimethoxyethane containing naphthalene,1-(N,N-dimethylamino)-naphthalene or 4,4'-di-t-butylbiphenyl in anamount of at least 1 mole per mole of the alkali metal or the alkalineearth metal. Tetrahydrofuran containing naphthalene or4,4'-di-t-butylbiphenyl is most preferred. The amount of the solvent maybe one sufficient to make the reaction proceed smoothly. Usually, it is1 to 100 times, preferably 2 to 20 times, the volume of the startingcompound.

The reaction temperature is from -100° C. to +100° C., preferably -78°to +50° C., especially preferably -78° C. to 0° C. The reaction timevaries depending upon the reaction temperature. Usually, the reactionends within several hours at -78° to 0° C.

Zinc may also be used favorably as the metal species of the reducingagent. The cyclization using zinc is ordinarily carried out in thepresence of trimethylchlorosilane and a base. The amount of zinc is 1 to50 moles, preferably 10 to 30 moles, per mole of the propargylcyclopentane of formula [V]. Zinc is activated prior to use withhydrochloric acid, copper, silver, mercury, etc. Trimethylchlorosilaneis used in an amount of 1 to 20 moles, preferably 5 to 10 moles, permole of the compound of formula [V]. The base is used in an amount of 1to 10 moles, preferably 1 to 5 moles, per mole of the compound offormula [V].

The solvent for the cyclization reaction is preferably an ether solventsuch as diethyl ether, tetrahydrofuran and dimethoxyethane.Tetrahydrofuran is most preferred. The amount of the solvent may be onesufficient to make the reaction proceed smoothly. Usually, it is 1 to100 times, preferably 2 to 20 times, the volume of the startingcompound.

The reaction temperature employed is 0° to 100° C., preferably 20° to80° C. The reaction time varies depending upon the reaction temperature.Usually, the reaction ends within 30 minutes to 24 hours at atemperature of 20° to 80° C.

The resulting product can be taken out of the reaction system as a crudeproduct by quenching, extraction, etc. using a saturated aqueoussolution of ammonium chloride. As desired, the crude product can bepurified by purifying means such as column chromatography, thin layerchromatography, liquid chromatography and recrystallization.

The product obtained by cyclization using zinc is a compound of thefollowing formula ##STR22## wherein R²¹, R⁴, R⁵, R³¹ and n are asdefined above, its enantiomorph, or a mixture of both in an arbitraryratio.

The trimethylsilyl ether at the 2-position of the resulting6,7-disubstituted-3-methylene-2-trimethylsilyloxybicyclo[3.3.0]octanemay be hydrolyzed to 2-hydroxyl by using an ordinary reagent forsplitting off trimethylsilyl ether such as tetrabutyl ammonium fluoride(tetrahydrofuran as a solvent), p-toluenesulfonic acid (methanol as asolvent), potassium carbonate (methanol as solvent), citric acid,(methanol as a solvent), and p-toluenesulfonic acid/pyridine (methanolas a solvent). In other words, by carrying out the reaction in the samemanner as the deprotecting reaction to be described below, the compoundcan be converted to the desired one. When a protected hydroxyl groupexists at the 3'-position (or the 4'-position) of the 7- and 6-positionsof the propargyl cyclopentane of formula [V] and the6,7-disubstituted-2-hydroxy-3-methylenebicyclo[3.3.0]octane of formula[VI], it may be deprotected, as required, to form a free hydroxyl group.

If the protective group for the hydroxyl group is a group forming anacetal linkage together with the oxygen atom of the hydroxyl group, itmay be eliminated conveniently by using acetic acid, a pyridinium saltof p-toluenesulfonic acid, a cation exchange resin, etc. as a catalystand water, tetrahydrofuran, diethyl ether, dioxane, acetone,acetonitrile, etc. as a reaction solvent. The deprotecting reaction iscarried out usually at -78° to +30° C. for about 10 minutes to 3 days.When the protective group is a tri(C₁ -C₇)hydrocarbon-silyl group, itcan be eliminated by carrying out the reaction at the same temperaturein the same reaction solvent as described above in the presence ofacetic acid, tetrabutyl ammonium fluoride, cesium fluoride, hydrogenfluoride or pyridinehydrogen fluoride.

The compounds of formulae [V] and [VI] include stereoisomers since thecarbon atom of the cyclopentane ring which is substituted by OR²¹ offormyl or propargyl or ω-chain functional group (in the case of [V]),and the carbon atoms (1-, 2-, 5-, 6-, 7-positions of [VI]) of thebicyclo[3.3.0]octane ring, and the carbon atom which is substituted byOR³¹ of ω-side chain are asymmetric. The compounds of this inventioninclude any of these stereoisomers, and mixtures thereof in arbitraryratios. Of these, compounds having a steric structure expressed by theformula are most preferred.

The processes of this invention for obtaining the isocarbacyclins offormula [I] have various advantages among which are:

(1) Starting materials which are easily available industrially can beused.

(2) Synthesis of the skeleton in accordance with the processes of theinvention proceeds regiospecifically, and the yields of the products arehigh.

The novel isocarbacyclins of formula [I] are expected to haveisocarbacyclin-like activities such as platelet aggregation inhibitoryactivity, vasodilating activity, antihypertensive activity and cellprotecting activity, and are useful as intermediates for synthesis ofisocarbacyclin which has a good prospect of use as a medicine.

The compound of formula [I], its enantiomorph or a mixture of thecompound and its enantiomorph in an arbitrary ratio can be converted toa 9(O)-methanoprostacyclin which is a compound represented by thefollowing formula [VII] ##STR23## wherein R¹² represents a hydrogen atomor a C₁ -C₄ alkyl or alkenyl group, R²² and R³² are identical ordifferent and each represents a hydrogen atom, a tri(C₁-C₇)hydrocarbon-silyl group or a group forming an acetal linkagetogether with the oxygen atom of the hydroxyl group, and R⁴, R⁵ and nare as defined above, its enantiomorph or a mixture of both in anarbitrary ratio.

Specific examples of the C₁ -C₄ alkyl or alkenyl group for R¹² may bethe same as those exemplified with regard to R¹ in formula [I]. Specificexamples of the hydroxy-protecting groups for R²² and R³² are also thesame as those exemplified with regard to R² and R³ in formula [I].

This desulfonation is carred out by reacting the compound of formula [I]with an alkali metal amalgam as a reducing agent. Basically, thisreaction is carried out in accordance with the method of Trost et al.,Tetrahedron Letters, 3477 (1976). Specifically, sodium amalgam ispreferably used as the alkali metal amalgam, and sodium amalgamcontaining 1 to 20%, preferably 2 to 10%, of sodium is especiallypreferably used. The amount of the amalgam is used in an amount of 5 to500 moles, preferably 50 to 500 moles, per mole of the 5-arylsulfonylisocarbacyclin. The reaction temperature is -79° to +100° C., preferably-40° to +30° C. The reaction time varies depending upon the reactiontemperature, and for example, a period of about 4 hours is sufficient at-10° C. This reaction is carried out in the presence of 1 to 10 moles,per mole of the compound of formula [I], of disodium phosphate.

The reaction is carried out in an organic solvent. Examples of theorganic solvent are hexane, benzene, toluene, diethyl ether,tetrahydrofuran, dimethoxyethane, dioxane, N,N-dimethylformamide,methanol and ethanol. Methanol is preferred. The amount of the organicsolvent may be one sufficient to make the reaction proceed smoothly.Usually, it is 1.0 to 100 times, preferably 5.0 to 50 times, the volumeof the reactant.

The resulting reaction mixture may be worked up by ordinary methods. Forexample, a difficultly water-soluble organic solvent such as hexane,pentane, petroleum ether, diethyl ether and ethyl acetate is added tothe reaction mixture. As required, the resulting mixture is washed with,for example, aqueous sodium chloride solution, and dried over adesiccant such as anhydrous magnesium sulfate, anhydrous sodium sulfateand anhydrous calcium chloride. The organic solvent is removed underreduced pressure to give a crude product. As desired, the crude productcan be purified by purifying means such as column chromatography, thinlayer chromatography and liquid chromatography.

The above desulfonation reaction may be carried out by a known method[cf. A. C. Brown et al., J. Org. Chem., 50, 1749 (1985)] using magnesiummetal as the reducing agent insteacd of the alkali metal amalgam.

The resulting product may, as required, be subjected to deprotectingreaction and hydrolysis reaction to finally give an isocarbacyclin whichis the compound of formula [VII], its enantiomorph or a mixture of bothin an arbitrary ratio.

If the protective group for the hydroxyl group is a group forming anacetal linkage together with the oxygen atom of the hydroxyl group, itmay be eliminated conveniently by using acetic acid, a pyridinium saltof p-toluenesulfonic acid, a cation exchange resin, etc. as a catalystand water, tetrahydrofuran, diethyl ether, dioxane, acetone,acetonitrile, etc. as a reaction solvent. The deprotecting reaction iscarried out usually at -78° to +30° C. for about 10 minutes to 3 days.When the protective group is a tri(C₁ -C₇)hydrocarbon-silyl group, itcan be eliminated by carrying out the reaction at the same temperaturein the same reaction solvent as described above in the presence ofacetic acid, tetrabutyl ammonium fluoride, cesium fluoride, hydrogenfluoride or pyridinehydrogen fluoride.

As a result, the isocarbacyclins of formula [VII] which have a goodprospect of utility as medicines can be obtained from the arylsulfonylisocarbacyclins of formula [I] as starting materials.

The compounds of formula [V] can be produced from a4-substituted-2-cyclopentenone as a starting material. A process forproducing the compound of formula [V] is included within a process (tobe described below as one embodiment of the invention) for producing apropargyl cyclopentane which is a compound represented by the followingformula [VIII] ##STR24## wherein R⁴, R⁵ and n are as defined above, R²³and R³³ are identical or different and each represents a tri(C₁-C₇)hydrocarbon-silyl group or a group forming an acetal linkagetogether with the oxygen atom of the hydroxyl group, R⁸ represents ahydrogen atom or a C₁ -C₆ saturated or unsaturated aliphatic hydrocarbongroup which may be substituted by a (C₁ -C₆ alkyl)oxycarbonyl group or ahydroxyl group which may be protected, its enantiomorph or a mixture ofboth in an arbitrary ratio ([VIII] in which R⁸ is a hydrogen atomcorresponds to [V]).

As one embodiment, the present invention also provides a process forproducing a propargylcyclopentane which is a compound represented by thefollowing formula [VIII] ##STR25## wherein R²³, R³³, R⁴, R⁵, R⁸ and nare as defined above, which comprises subjecting a4-substituted-2-cyclopentenone represented by the following formula [IX]##STR26## wherein R²⁴ represents a tri(C₁ -C₇)hydrocarbonsilyl group ora group forming an acetal linkage together with the oxygen atom of thehydroxyl group, to conjugation addition reaction with an organic coppercompound formed from a vinyllithium represented by the following formula[X] ##STR27## wherein R³⁴ represents a tri(C₁ -C₇)hydrocarbonsilyl groupor a group forming an acetal linkage together with the oxygen atom ofthe hydroxyl group, and R⁴, R⁵ and n are as defined above, and a coppercompound represented by the following formula [Xa]

    Cu--Q                                                      [Xa]

wherein Q represents a halogen atom, a cyano group, a phenylthio groupor a 1-pentynyl group, reacting the resulting enolate intermediate witha propargyl halide represented by the following formula [XI]

    X .tbd.--R.sup.81                                          [XI]

wherein R⁸¹ represents a hydrogen atom, a trimethylsilyl group, or a C₁-C₆ saturated or unsaturated aliphatic hydrocarbon group which may besubstituted by a (C₁ -C₆ alkyl)oxycarbonyl group or a hydroxyl groupwhich may be protected, and X repesents an iodine or bromine atom, inthe presence of an organotin compound represented by the followingformula (Xb)

    R.sub.3 SnY                                                (Xb)

wherein three R's are identical or different and each represents a C₁-C₄ alkyl group, a C₃ -C₇ cycloalkyl group or a halogen atom, Yrepresents a halogen atom or a trifurate group, provided that two orthree R's are not simultaneously halogen atoms, to thereby form analpha, beta, gamma-trisubstituted cyclopentanone represented by thefollowing formula [XII] ##STR28## wherein R²⁴, R³⁴, R⁴, R⁵, R⁸¹ and nare as defined above, thereafter treating the trisubstitutedcyclopentanone with a methylenation agent prepared from titaniumtetrachloride, zinc and a dihalomethane to form an alpha, beta,gamma-trisubstituted methylenecyclopentane represented by the followingformula [XIII] ##STR29## wherein R²⁴, R³⁴, R⁴, R⁵, R⁸¹ and n are asdefined above, hydroborating and subsequently oxidizing thetrisubstituted methylenecyclopentane to form an alpha, beta,gamma-trisubstituted hydroxymethylcyclopentane represented by thefollowing formula [XIV-a] ##STR30## wherein R²⁴, R³⁴, R⁴, R⁵, R⁸¹ and nare as defined hereinabove, subsequently, when R⁸¹ is a trimetsilylgroup, selectively deprotecting the tri-substituhydroxymethylcyclopentane with sodium methoxide torm a compound of thefollowing formula [XIV-b] ##STR31## wherein R²⁴, R³⁴, R⁴, R⁵ and n areas defined above, R⁸ repesents a C₁ -C₆ saturated or unsaturatedaliphatic hydrocarbon group which may be substituted by a (C₁ -C₆alkyl)oxycarbonyl group or a hydroxyl group which may be substituted,further oxidizing the resulting compound, and if required, subjecting itto deprotecting reaction.

As the compound of formula [V] corresponding to the compound of formula[VIII] in which R⁸ represents a hydrogen atom is cyclized to form thecompound of formula [VI], a compound of formula [VIII] in which R⁸, R²³,and R³³ are not hydrogen atoms, for example a compound of the followingformula [VIII'] ##STR32## wherein R⁴, R⁵, R²⁴, R³⁴ and n are as definedabove, R⁸¹¹ represents a hydrogen atom or an aliphatic hydrocarbon groupwhich may be substituted by a hydroxyl group which may be protected, andm is 0 or 1, can be cyclized under the same operating conditions asabove to form a compound of the following formula [VIII"] ##STR33##wherein R⁴, R⁵, R²⁴, R³⁴, R⁸¹¹, m and n are as defined above.

An isocarbacyclin which is a compound represented by the followingformula [XIX] ##STR34## wherein R⁴, R⁵, R⁸, R²⁴, R³⁴ and n are asdefined above, its enantiomorph, or a mixture of both in an arbitraryratio can be produced by reacting the compound of formula [VIII] with alithium compound represented by the following formula [XVa] or [XVb]

    R.sup.41 R.sup.42 R.sup.43 SiLi                            XVa]

    (R.sup.41 R.sup.42 R.sup.43 Si).sub.q (L).sub.2-q CuLi     [XVb]

wherein R⁴¹, R⁴² and R⁴³ are identical or different and each representsa C₁ -C₇ hydrocarbon group, L represents a cyano, phenylthio or1-pentynyl group, and q represents 1 ro 2, treating the product withcarbon disulfide, reacting the treated compound with a halogen compoundrepresented by the following formula [XVI]

    R.sup.9 X                                                  [XVI]

wherein R⁹ represents a methyl or ethyl group, and X represents ahalogen atom, to form a 9-substituted-5,6-dehydroPGE₂ which is acompound represented by the following formula [XVII] ##STR35## whereinR⁴, R⁵, R⁸, R⁴¹, R⁴², R⁴³, R²⁴, R³⁴ and n are as defined above, itsenantiomorph or a mixture of both in an arbitrary ratio, reacting thiscompound with tri-n-butyltin hydride in the presence of t-butyl peroxideto form a silylated carbacyclin which is a compound represented by thefollowing formula [XVIII] ##STR36## wherein R⁴, R⁵, R⁸, R¹¹, R²⁴, R³⁴,R⁴¹, R⁴², R⁴³ and n are as defined above, and shows that the stericconfiguration of the double bond is E, Z or a mixture of E and Z, itsenantiomorph or a mixture of both in an arbitrary ratio, treating thesilylated carbacyclin with an acid, and if required, subjecting thetreated compound to deprotecting reaction, hydrolysis reaction and/orsalt-forming reaction.

The above process starts with the reaction of the compound of formula[VIII] with the lithium compound of formula [XVa] or [XVb] in an organicmedium. In formula [XVa], R⁴¹, R⁴² and R⁴³ are identical or differentand each represents a C₁ -C₇ hydrocarbon group, such as methyl, ethyl,propyl, butyl, 1-butyl, phenyl and tolyl groups. The methyl, t-butyl andphenyl groups are especially preferred. Most preferred specific examplesof the above lithium compound are dimethylphenylsilyl lithium andbis(dimethylphenyl)copper lithium. The amount of the lithium compoundused is 0.8 to 5 moles, preferably 0.9 to 3 moles, per mole of thecompound of formula [VIII]. The organic medium for making the reactionproceed smoothly may be an organic medium inert to the lithium compound.Examples of the organic medium are ethers such as diethyl ether,tetrahydrofuran and dioxane, hydrocarbons such as pentane and hexane,and mixtures of these. Tetrahydrofuran is preferred. The reactiontemperature is -100° to 0° C., preferably - 78° to -40° C. Usually, aperiod of about 5 minutes to 30 minutes is sufficient as the reactiontime. After the reaction, a polar medium such as hexamethylphosphorictriamide (HMPA) or 1,3-dimethyl-2-imidazoline (DMI) is added to thereaction mixture in an amount of about 1 to 20 moles, preferably 5 to 10moles, per mole of the starting material [VIII] used. Then, carbondisulfide is added to the mixture. The amount of carbon disulfide usedis 0.8 to 10 moles, preferably 0.9 to 6 moles. After the addition ofcarbon disulfide, the reaction temperature of the reaction mixture israised, and the reaction is carried out at -10° to +10° C., preferably0° to 5° C. A period of 30 minutes to 2 hours usually suffices as thereaction time. Then, the halogen compound of formula [XVI] is added tothe reaction mixture, and the reaction is carried out to completion. Inthe halogen compound, the halogen atom X is, for example, an iodine orbromine atom. R⁹ is, for example, a methyl or ethyl group. Methyl iodideis an especially preferred example of the halogen compound. The amountof the halogen compound used is 0.8 to 10 moles, preferably 0.9 to 6moles, per mole of the starting material [VIII] used. The reactiontemperature and time are the same as in the treatment with carbondioxide. After the reaction, the reaction mixture is worked up in acustomary manner. Specifically, the reaction mixture is mixed with asaturated aqueous solution of ammonium chloride or a saturated aqueoussolution of ammonium sulfate and then with a difficultly water-solubleorganic solvent such as hexane, pentane, petroleum ether, diethyl etheror ethyl acetate. As required, the resulting mixture is washed with, forexample, an aqueous solution of sodium chloride, and dried over adesiccant such as anhydrous magnesium sulfate, anhydrous sodium sulfateor anhydrous calcium chloride. The organic medium is removed underreduced pressure to give a crude product. If desired, the crude productcan be purified by purifying means such as column chromatography,thin-layer chromatography and liquid chromatography. As a result, the9-substituted-5,6-dehydroPGE₂ represented by formula [XVII] is produced.

The reaction in the second step is cyclization involving treating thecompound of formula [XVII] with tri-n-butyltin hydride and t-butylperoxide. The amount of tri-n-butyltin hydride used is 50 to 0.8 mole,preferably 10 to 1 mole, per mole of the starting material [XVIII], andthe amount of t-butyl peroxide used is 0.5 to 0.005 mole, preferably 0.1to 0.01 mole, per mole of the starting material [XVII]. The reactiontemperature is 0° to 120° C., preferably 50° to 100° C. The reactiontime, which varies depending upon the reaction temperature, is usuallyabout 40 hours at a reaction temperature of 70° C. An organic medium maybe used in order to make the reaction proceed smoothly. Examples of theorganic medium are aromatic hydrocarbons such as benzene and toluene,saturated hydrocarbons such as hexane, heptane and octanes, and mixturesthereof. Benzene is preferred. After the reaction, the reaction mixtureis concentrated under reduced pressure. The crude reaction mixture issubjected to purifying means such as chromatography. Preferably, it issubjected to a purifying step after the peroxide which may possiblyremain is decomposed with sodium thiosulfate, sodium sulfite, etc. As aresult, the silylated carbacyclin of formula [XVIII] is produced.

The reaction in the third step is desilylation by treating the silylatedcarbacyclin of formula [XVIII] with an acid. Trifluoroacetic acid,acetic acid-boron trifluoride, sulfuric acid and hydriodic acid areexamples of the acid used in desilylation. Trifluoroacetic acid isespecially preferably used.

The amount of the acid used is 0.8 to 50 moles, preferably 1 to 30moles, per mole of the silylated carbacyclin. The reaction temperatureis 0° to 100° C., preferably 10° to 30° C. The reaction time variesdepending upon the reaction temperature. Usually, a period of 10 minutesto 3 hours suffices. An organic medium may be used in order to make thereaction proceed smoothly.

Examples of the medium are halogenated hydrocarbons such asdichloromethane, dichlolroethane and chloroform. Dichloromethane isespecially preferred. After the reaction, the reaction mixture istreated in a customary manner as in the first step described above. Ifrequired, the resulting product is subjected to deprotecting reaction,hydrolysis reaction and/or salt-forming reaction to give anisocarbacyclin which is a compound of the formula [XIX], itsenantiomorph or a mixture of both in an arbitrary ratio.

According to this invention, the compound containing a carboxyl groupformed by the hydrolysis reaction can, as required, be subjected tosalt-forming reaction to give the corresponding carboxylate. Thesalt-forming reaction is known per se. The carboxylate can be formed byneutralizing the carboxylic acid compound by an ordinary method with abasic compound such as potassium hydroxide, sodium hydroxide or sodiumcarbonate, ammonia, trimethylamine, monoethanolamine, or morpholine inan amount nearly equal to the carboxylic acid compound.

According to the embodiment described above, the isocarbacyclin offormula [XIX] can be easily obtained by less process steps than in theprior art from the starting 9-deoxy-9-formyl-5,6-dehydroPGE₂ of formula[VIII] through a new intermediate by quite a new cyclizing method. Theprocess in this embodiment, therefore, has a great industrialsignificance. The silylated carbacyclin of formula [XVIII], theintermediate, is a novel substance to the best of the knowledge of thepresent inventor. This compound is expected to have prostacyclin-likeactivities or lipoxygenase activity. The compound of formula [V]corresponding to the intermediate of formula [VIII] in which R⁸ is ahydrogen atom is a novel intermediate for production of the novelcarbacyclin or isocarbacyclin as described above.

The following Examples illustrate the present invention in greaterdetail. It should be understood however that the invention is notlimited thereto. In the following examples, --OZ represents at-butyldimethylsilyloxy group [--OSi.t--Bu.(CH₃)₂ ], and --OZ'represents a trimethylsilyloxy group [OSi(CH₃)₃ ].

EXAMPLE 1 ##STR37##

To a solution of 59 mg (1.05 mmole) ofmethyl-4,4-bis(phenylsulfonyl)butanoate in 0.8 ml of tetrahydrofuran(THF hereinafter) was added 6.2 mg (0.15 mmole) of NaH (60% in oil) in astream of nitrogen, and the mixture was stirred for 1 hour. A solutionof 68 mg (0.12 mmole) of an acetate compound represented by formula (1)above in 0.8 ml of THF was added, and then 6.3 mg (0.007 mmole) ofbis[bis(1,2-diphenylphosphono)ethane]palladium (O) was added. Themixture was stirred at room temperature for 3 hours and then at 60° C.for 4 hours. After the reaction, a saturated aqueous solution ofammonium chloride was added to terminate the reaction. The reactionmixture was extracted with ethyl acetate. The organic layer was washedwith water, saturated aqueous sodium chloride solution, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The crude product was subjected to silica gel column chromatography(hexane/ethyl acetate=20:1→10:1) to give 64 mg (50%) of4,4-bis(phenylsulfonyl)isocarbacyclin-11,15-bis(t-butyldimethylsilyl)ethermethyl ester and 23 mg (34%) of the recovered acetate.

IR (cm⁻¹, neat): 2950, 2860, 1740, 1580, 1460, 1440, 1330, 1310, 1255,1140.

NMR (δppm, CDCl₃): 0.9 (s+m, 21H), 1.2-2.4 (m, 14H), 2.6-3.1 (m, 7H),3.7 (s, 3H), 3.75 (m, 1H), 4.05 (m, 1H), 5.4 (m, 2H), 5.55 (m, 1H),7.1-8.0 (m, 10H).

EXAMPLE 2 ##STR38##

The disilyl compound (2) (87 mg; 0.10 mmole) was dissolved in 2 ml ofdry THF, and 470 microliters (0.47 mmole) of a 1.0M THF solution oftetrabutyl ammonium fluoride was added, and the mixture was stirred atroom temperature for 10 hours. Water was added, and the reaction mixturewas extracted with ethyl acetate, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure. The residuewas subjected to silica gel column chromatography (ethyl acetate, 2%methanol) to give 51 mg (79%) of the desilylated compound (3).

NMR (δppm, CDCl₃): 0.9 (m, 3H), 1.2-2.4 (m, 14H), 2.6-3.1 (m, 7H), 3.65(s, 3H), 3.65-4.05 (m, 2H), 5.4 (m, 2H), 5.55 (m, 1H), 7.1-8.0 (m, 10H).

EXAMPLE 3 ##STR39##

A solution of 116 mg (0.2 mmole) of the acetate of formula (4) above in1 ml of THF was added to a solution of 94 mg (0.22 mmole) ofmethyl-4,4-bis(phenylsulfonyl)butanoate treated with 8.8 mg (60% in oil,0.22 mmole) of NaH in a nitrogen stream in 1 ml of THF. Then, 13 mg(0.011 mmole) of tetrakis(triphenylphosphine)palladium (O) was added,and the mixture was stirred at 60° C. for 7 hours. After the reaction, asaturated aqueous solution of sodium chloride was added to terminate thereaction. The reaction mixture was extracted with ethyl acetate. Theorganic layer was washed with water and a saturated aqueous sodiumchloride solution, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The crude product was subjected tosilica gel column chromatography (hexane:ethyl acetate=-20:1→10:1) togive 128 mg (71%) of17(S),20-dimethyl-4,4-bis(phenylsulfonyl)isocarbacyclin disilyl ethermethyl ester (5).

NMR (δppm, CDCl₃): 0.9 (s+m, 21H), 1.0-2.4 (m, 18H), 2.6-3.1 (m, 7H),3.65 (s, 3H), 3.7-4.1 (m, 2H), 5.3-5.6 (m, 3H), 7.1-8.0 (m, 10H).

EXAMPLE 4 ##STR40##

A solution of 78 mg (0.15 mmole) of the acetate of formula (6) above in1 m of THF was added to a solution of 65 mg (0.17 mmole) ofmethyl-4,4-bis(phenylsulfonyl)butanoate treated with 6.8 mg (60% in oil,0.17 mmole) of NaH in a nitrogen stream in 1 ml of THF. Then, 7.2 mg(0.008 mmole) of bis[bis(1,2-diphenylphosphino)ethane]palladium (O) wasadded, and the mixture was stirred at 80° C. Five hours after startingof stirring of the mixture, 7.2 mg (0.008 mmole) of the above palladium(O) compound was further added and the mixture was stirred for 5 hours.After the reaction, a saturated aqueous solution of ammonium chloridewas added to terminate the reaction. The reaction mixture was extractedwith ethyl acetate. The organic layer was washed with water andsaturated aqueous sodium chloride solution, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The crudeproduct was subjected to silica gel column chromatography(n-hexane:ethyl acetate=20:1→10:1) to give 92 mg (78%) of the aboveproduct (7).

NMR (δppm CDCl₃): 0.9 (s+m, 12H), 1.1-2.4 (m, 14H), 1.1 (s, 3H), 2.6-3.1(m, 7H), 3.65 (s, 3H), 3.8 (m, 1H), 5.3-5.6 (m, 3H), 7.1-8.0 (m, 10H).

EXAMPLE 5 ##STR41##

A solution of 110 mg (0.2 mmole) of the acetate compound representd byformula (8) above in 1 ml of DMF was added to a solution of 84 mg (0.22mmole) of methyl-4,4-bis(phenylsulfonyl)butanoate treated with 9 mg(0.23 mmole, 60% in oil) of NaH in a nitrogen stream in 1 ml of THF, andthen 9 mg (0.01 mmole) of bis[bis(1,2-diphenylphosphino)ethane]palladium(O) was added. The mixture was stirred at 60° C. for 5 hours. After thereaction, a saturated aqueous solution of ammonium chloride was added toterminate the reaction. The reaction mixture was extracted with ethylacetate. The organic layer was washed with water and saturated aqueoussodium chloride solution, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The crude product was subjected tosilica gel column chromatography (n-hexane:ethyl acetate=20:1→10:1) togive 113 mg (65%) of the product of formula (9).

NMR (δppm CDCl₃): 0.9 (s, 18H), 1.0-2.4 (m, 15H), 2.6-3.0 (m, 7H), 3.70(s, 3H), 3.6-4.1 (m, 2H), 5.3-5.6 (m, 3H), 7.1-8.0 (m, 10H).

EXAMPLE 6 ##STR42##

48 g (0.075 mmole) of 4,4-bis(phenylsulfonyl)isocarbacyclin methyl ester(3) was dissolved in a mixture of 3 ml of THF, 1.5 ml of methanol and 1ml of water, and 60 mg of lithium hydroxide hydrate was added to thesolution. The mixture was stirred at room temperature for 20 hours.Aqueous ammonium chloride solution was added, and the solvent wasevaporated under reduced pressure. The residue was acidified with dilutehydrochloric acid to a pH of 3 to 4, and then extracted with ethylacetate. The organic layer was washed with aqueous sodium chloridesolution, dried over anhydrous magnesium sulfate, and concentrated. Thecrude product was purified by column chromatography (hexane:aceticacid=1:4) to give 40 mg (85%) of the carboxylic acid of formula (10).

NMR (δppm, CDCl₃): 0.9 (m, 3H), 1.2-2.4 (m, 14H), 2.6-3.1 (m, 7H),3.6-4.1 (m, 2H), 5.4 (m, 2H), 5.6 (m, 1H), 7.1-8.0 (m, 10H).

EXAMPLE 7 ##STR43##

A solution of 70 mg (0.13 mmole) of the acetate compound represented byformula (11) in 0.8 ml of THF was added to a solution of 57 mg (0.15mmole) of methyl-4,4-bis(phenylsulfonyl)butanoate treated with 6 mg ofNaH (60% in oil, 0.15 mmole) in a nitrogen stream in 0.8 ml of THF, andthen 6.3 mg (0.007 mmole) ofbis[bis(1,2-diphenylphosphino)ethane]palladium (O) was added. Themixture was stirred at 70° C. for about 15 hours. After the reaction,saturated ammonium chloride solution was added to terminate thereaction. The reaction mixture was extracted with ethyl acetate, and theorganic layer was washed with water and saturated aqueous sodiumchloride solution, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The crude product was subjected tosilica gel column chromatography (n-hexane:ethyl acetate=20:1→5:1) togive 89 mg (79%) of the product (12).

NMR (δppm, CDCl₃): 0.9 (s+m, 12H), 1.1-2.4 (m, 14H), 2.6-3.1 (m, 7H),3.65 (s, 3H), 3.8 (m, 1H), 4.7-5.6 (m, 6H), 7.1-8.0 (m, 10H).

EXAMPLE 8 ##STR44##

In the same way as in Example 7, the above compound was synthesized fromthe corresponding acetate and methyl-4,4-bis(phenylsulfonyl)butanoate.

Yield: 75%.

NMR (δppm, CDCl₃): 0.9 (s+m, 21H), 1.0-2.4 (m, 16H), 1.13 (s, 6H), 3.65(s, 3H), 3.7-4.1 (m, 2H), 5.3-5.6 (m, 3H), 7.1-8.0 (m, 10H).

EXAMPLE 9 ##STR45##

In the same way as in Example 7, the above compound was synthesized fromthe corresponding acetate and methyl-4,4-bis(phenylsulfonyl)butanoate.

Yield: 74%.

NMR (δppm, CDCl₃): 0.9 (s, 18H), 1.0-2.4 (m, 17H), 2.6-3.0 (m, 7H), 3.70(s, 3H), 3.6-4.1 (m, 2H), 5.3-5.6 (m, 3H), 7.1-8.0 (m, 10H).

EXAMPLE 10 ##STR46##

In the same way as in Example 7, the above compound was synthesized fromthe corresponding acetate and methyl-4,4-bis(phenylsulfonyl)butanoate.

Yield: 83%.

NMR (δppm, CDCl₃): 0.9 (s+m, 21H), 1.0-2.4 (m, 18H), 2.6-3.1 (m, 7H),3.65 (s, 3H), 3.7-4.1 (m, 2H), 5.3-5.6 (m, 3H), 7.1-8.0 (m, 10H).

EXAMPLE 11 ##STR47##

73 mg (0.13 mmole) of the methoxycarbonyloxy compound (16) and asolution of 57 mg (0.15 mmole) ofmethyl-4,4-bis(phenylsulfonyl)butanoate and 5.8 mg (0.0065 mmole) ofbis[bis(1,2-diphenylphosphino)ethane]palladium (0) in 1 ml of THF werestirred at 50° C. for 4 hours in a stream of nitrogen. After thereaction, saturated aqueous ammonium chloride solution was added toterminate the reaction. The reaction mixture was extracted with ethylacetate, and the organic layer was washed with water and saturatedaqueous solution of sodium chloride, dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure. The crude product wassubjected to silica gel column chromatography (hexane:ethylacetate=20:1→10:1) to give 76 mg (68%) of4,4-bis(phenylsulfonyl)isocarbacyclin-11,15-bis(t-butyldimethylsilyl)ethermethyl ester (2).

IR (cm⁻¹, neat): 2950, 2860, 1740, 1580, 1460, 1440, 1330, 1310, 1255,1140.

NMR (δppm, CDCl₃): 0.9 (s+m, 21H), 1.2-2.4 (m, 14H), 2.6-3.1 (m, 7H),3.7 (s, 3H), 3.75 (m, 1H), 4.05 (m, 1H), 5.4 (m, 2H), 5.55 (m, 1H),7.1-8.0 (m, 10H).

EXAMPLE 12 ##STR48##

NaH [60% in oil; 44 mg (1.1 mmole)] was added at 0° C. to a solution of400 mg (1.05 mmole) of methyl-4,4-bis(phenylsulfonyl)butanoate in 2 mlof THF in a stream of nitrogen. The mixture was stirred for 1 hour, anda solution of 450 mg (0.82 mmole) of the acetate of formula (17) in 2 mlof THF was added to the mixture. Furthermore, 80 mg (0.09 mmole) ofbis[bis(1,2-diphenylphosphino)-ethane]palladium (O) was added, and themixture was stirred at 60° C. for 5 hours. After the reaction, saturatedaqueous ammonium chloride solution was added to terminate the reaction.The reaction mixture was extracted with ethyl acetate, and the organiclayer was washed with saturated aqueous sodium chloride solution, driedover anhydrous magnesium sulfate, and concentrated under reducedpressure. The crude product was subjected to silica gel columnchromatography (hexane:ethyl acetate=20:1→10:1) to give 493 mg (70%) of4,4-bis(phenylsulfonyl)isocarbacyclin-11,15-bis(t-butyldimethylsilyl)ethermethyl ester (2).

IR (cm⁻¹, neat): 2950, 2860, 1740, 1580, 1460, 1440, 1330, 1310, 1255,1140.

NMR (δppm, CDCl₃): 0.9 (s+m, 21H), 1.2-2.4 (m, 14H), 2.6-3.1 (m, 7H),3.7 (s, 3H), 3.75 (m, 1H), 4.05 (m, 1H), 5.4 (m, 2H), 5.55 (m, 1H),7.1-8.0 (m, 10H).

EXAMPLE 13 ##STR49##

A solution of 225 mg (0.44 mmole) of the allyl alcohol represented byformula (18) above in 2 ml of methylene chloride was cooled to 0° C.,and about 60 microliters (2 mmoles) of pyridine was added. Furthermore,78 microliters (1 mmole) of methyl chloroformate was added, and themixture was stirred for 1 hour. It was further stirred for 2 hours atroom temperature.

The reaction was terminated with water, and the reaction mixture wasextracted with diethyl ether. The organic layer was washed with aqeuouspotassium hydrogen sulfate, saturated aqueous hydrogen carbonatesolution and saturated aqueous sodium chloride solution in this order,and dried over anhydrous magnesium sulfate. The solvent was evaporatedunder reduced pressure, and the residue was subjected to silica gelcolumn chromatography (hexane:ethyl acetate=20:1) to give 246 mg (98%)of the methoxycarbonyloxy compound of formula (19).

IR (cm⁻¹, neat): 2950, 2860, 1755, 1460, 1440, 1360, 1260, 1120.

NMR (δppm, CDCl₃): 0.85 (s, 9H), 0.9 (s, 9H), 0.8-1.0 (m, 3H), 1.0-1.8(m, 8H), 1.8-2.5 (m, 6H), 3.0 (m, 1H), 3.8 (s, 3H), 3.7-4.2 (m, 2H), 4.7(br. s, 2H), 5.5 (m, 2H), 5.7 (br. s, 1H).

Then, 340 mg (0.6 mmole) of the resulting methoxycarbonyloxy compound(19) and a solution of a mixture of 298 mg (0.78 mmole) ofmethyl-4,4-bis(phenylsulfonyl)butanoate and 45 mg (0.05 mmole) ofbis[(1,2-diphenylphosphino)ethane]palladium (O) in 4 ml of THF werestirred at 60° C. for 6 hours. After the reaction, saturated aqueoussolution of ammonium chloride was added to terminate the reaction. Thereaction mixture was extracted with ethyl acetate, and the organic layerwas washed with water and saturated aqeuous sodium chloride solution,dried over anhydrous magnesium sulfate, and concentrated under reducedpressure. The crude product was subjected to silica gel columnchromatography (hexane:ethyl acetate=20:1→10:1) to give 157 mg (30%) of4,4-bis(phenylsulfonyl)isocarbacyclin-11,15-bis(t-butyldimethylslyl)ethermethyl ester (2).

IR (cm⁻¹, neat): 2950, 2860, 1740, 1580, 1460, 1440, 1330, 1310, 1255,1140.

NMR (δppm, CDCl₃): 0.9 (s+m, 21H), 1.2-2.4 (m, 14H), 2.6-3.1 (m, 7H),3.7 (s, 3H), 3.75 (m, 1H), 4.05 (m, 1H), 5.4 (m, 2H), 5.55 (m, 1H),7.1-8.0 (m, 10H).

EXAMPLES 14-21

Example 13 was repeated except that each of the groups indicated inTable 1 was substituted for the dimethyl-t-butylsilyl group. Compoundsof formula (I) in which R² and R³ are as indicated in Table 1 wereobtained.

                  TABLE 1                                                         ______________________________________                                        Ex-       Group used instead of the                                           ample     dimethyl-t-butylsilyl group                                                                    R.sup.2 and R.sup.3                                ______________________________________                                        14        tribenzylsilyl group                                                                           same as left                                       15        triethylsilyl group                                                                            same as left                                       16        t-butyldiphenylsilyl group                                                                     same as left                                       17        dimethylphenylsilyl group                                                                      same as left                                       18        methoxymethyl group                                                                            same as left                                       19        1-ethoxyethyl group                                                                            same as left                                       20        2-methoxy-2-propyl group                                                                       same as left                                       21        tetrahydropyranyl group                                                                        same as left                                       ______________________________________                                    

EXAMPLE 22 ##STR50##

Metallic lithium (15 mg) and 266 mg of naphthalene were added to 7 ml ofTHF, and the mixture was stirred at room temperature for 2 hours toprepare a dark green anion radical solution. The solution was cooled to-50° C., and a solution of 50 mg of the compound (20) in 3 ml of THF wasadded. Five minutes later, saturated aqeuous ammonium chloride solutionwas added to quench the reaction mixture. The reaction mixture wasextracted with ethyl acetate, and the organic layer was washed withsaturated aqueous sodium chloride solution, dried over magnesiumsulfate, and concentrated under reduced pressure to give 246 g of acrude product. The crude product was chromatographed on a silica gelcolumn using a 9:1 mixture of hexane and ethyl acetate as an eluent togive 34 mg of the compound (21) in a yield of 67%.

The compound (21) consisted of 14 mg of the compound (21α) and 20 mg ofthe compound (21β) below. ##STR51##

NMR (δ_(TMS) ^(CDCl).sbsp.3) for both (21α) and (21β) 0.8-1.0 (21H, m),3.5-4.2 (4H, br), 4.91 (1H, brs), 5.01 (1H, brs), 5.43 (2H, m).

Rf (silica gel thin layer chromatography; developing solvent:n-hexane/ethyl acetate=4/1): (21α): 0.43, (21β): 0.30.

EXAMPLE 23

Metallic lithium (15 mg), 553 mg of 4,4'-di-t-butylbiphenyl and 5 ml ofTHF were stirred at 0° C. for 18 hours to prepare a dark green anionradical solution. The solution was cooled to -50° C., and a solution of50.6 mg of the compound (20) in 3 ml of THF was added. Five minuteslater, the reaction mixture was quenched, and then worked up as inExample 22 to give 30 mg of the compound (21) [(11 mg of (21α) and 19 mgof (21β)]. The yield of compound (21) was 59%.

EXAMPLE 24

Metallic sodium (14 mg), 85 mg of naphthalene and 2 ml of THF werestirred at room temperature for 2.5 hours to prepare an anion radicalsolution. The solution was cooled to -70° C., and a solution of 51 mg ofthe compound (20) in 1.2 ml of THF was added. The mixture was stirred at-70° C. for 1 hour, and the reaction mixture was quenched with saturatedaqueous ammonium chloride solution and worked up as in Example 22 togive 25 mg of the compound (21) [7 mg of (21α) and 18 mg of (21β)]. Theyield of the compound (21) was 42%.

EXAMPLE 25

A flask holding 28 mg of metallic sodium was cooled to -70° C. in anitrogen atmosphere, and about 7 ml of liquid ammonia was taken into theflask, and the mixture in the flask was concentrated with stirring. Asolution of 51 mg of the compound (20) in 3.5 ml of THF was added at-45° C., and the mixture was stirred for 50 minutes. Then, 432 mg ofsodium benzoate was added, and the mixture was stirred for 20 minutes togasify ammonia. Water was added, and the reaction mixture was extractedtwice with diethyl ether. The organic layer was washed with saturatedaqueous solution of sodium hydrogen carbonate, saturated aqueousammonium chloride solution and aqueous sodium chloride solution in thisorder, dried over anhydrous magnesium sulfate, and concentrated underreduced pressure to give 48 mg of a crude product. The crude product waschromatographed on a column of silica gel using a mixture of n-hexaneand ethyl acetate in a ratio of 87.5:2.5 to give 10 mg of the compound(21) [only (21β)]. Yield: 20%.

EXAMPLE 26 ##STR52##

Zinc dust was stirred for 5 minutes in 10% hydrochloric acid. Thesupernatant was removed by decantation, and the residue was washed oncewith water, three times with acetone and twice with diethyl ether, andthen dried in vacuum for 2 hours to activate it. To 53 mg of thecompound (20) was added 138 mg of this zinc dust, and further, asolution of 68 mg of trimethylchlorosilane in 1 ml of THF was added.Furthermore, 32 mg of 2,6-lutidine was added, and the mixture wasrefluxed for 4 hours. The reaction mixture was separated into a solidand a liquid by decantation. Ten milliliters of diethyl ether was addedto the liquid, and the organic layer was washed with saturated aqueouspotassium hydrogensulfate solution, saturated aqueous sodium chloridesolution and aqueous sodium chloride solution in this order, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The resulting crude product containing the compound (22) was dissolvedin 3 ml of methanol, and a small amount of pyridinium p-toluenesulfonatewas added. The mixture was stirred at room temperature for 10 minutes.Saturated aqueous sodium bicarbonate solution was added, and the mixturewas concentrated under reduced pressure to evaporate methanol. Theresidue was extracted with diethyl ether, and the organic layer waswashed with aqueous sodium chloride solution, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The crudeproduct was subjected to silica gel column chromatography using a 19:1mixture of n-hexane and ethyl acetate as an eluent to give 11.g mg ofthe compound (21) in a yield of 23%.

EXAMPLE 27

Zinc dust was stirred for 1 minute in 3% hydrochloric acid, and thiswashing was repeated four times. It was further washed five times withdistilled water, twice with 2% aqueous copper sulfate solution, further5 times with distilled water, four times with anhydrous ethanol, andfive times with diethyl ether. The product was filtered by a glassfilter in a stream of nitrogen gas, and dried under reduced pressure for4 hours to activate it.

To 53 mg of the compound (20) were added 138 mg of the activated zincdust, a solution of 68 mg of trimethylchlorosilane in 1 ml of THF, andthe mixture was refluxed for 4 hours.

The reaction mixture was worked up, desilylated and purified as inExample 26 to give 16 mg (yield 31%) of the compound (21).

EXAMPLE 28

Zinc dust (350 mg) was stirred in 10% hydrochloric acid for 4 minutes,and the supernatant was removed by decantation. The residue was washedwith acetone and then with diethyl ether, and a suspension of 12 mg ofsilver acetate in 1.7 ml of boiling acetic acid was added, and themixture was stirred for 1 minute. The supernatant was removed by asyringe, and the product was washed with 1 ml of acetic acid, threetimes with 2 ml of diethyl ether, 2 ml of methanol, further four timeswith 2 ml of diethyl ether and 4 times with 2 ml of THF, and dried invacuum for 3 hours to activate it.

To 53 mg of the compound (20) were added 138 mg of the activated zincdust, a solution of 68 mg of trimethylchlorosilane in 1 ml of THF, and32 mg of 2,6-lutidine, and the mixture was refluxed for 4 hours. Thereaction mixture was worked up, desilylated and purified as in Example26 to give 18 mg of the compound (21). Yield 34%.

EXAMPLE 29

Zinc dust (4.12 g) was stirred for 2 minutes in 10% hydrochloric acid,and the supernatant was removed by decantation. The residue was washedfour times with 5 ml of distilled water, and a solution of 0.8 g ofmercuric chloride in 5 ml of boiling water was added. The mixture wasstirred for 10 minutes. After removing the supernatant, the residue waswashed with 5 ml of distilled water, 7 times with 5 ml of ethanol, andfurther seven times with 5 ml of diethyl ether in this sequence, andthen dried in vacuum for 3 hours to prepare activated zinc dust.

To 53 mg of the compound (20) were added 138 mg of the activated zincdust, a solution of 68 mg of trimethylchlorosilane in 1 ml of THF and 32mg of 2,6-lutidine, and the mixture was refluxed for 4 hours. Thereaction mixture was worked up, desilylated and purified as in Example26 to give 17 mg of the compound (21). Yield 32%.

EXAMPLE 30 ##STR53##

Pyridine (5.05 ml) was dissolved in 50 ml of methylene chloride, and3.12 g of chromium trioxide was added. The mixture was stirred at roomtemperature for 20 minutes. A solution of 1.30 g of the compound (23) in3 ml of methylene chloride was added, and the mixture was stirred atroom temperature for 15 minutes. Diethyl ether (150 ml) was added, andthe mixture was suction-filtered thorugh Celite to remove the solid. Theorganic layer was washed with saturated aqueous potassiumhydrogensulfate and twice with aqueous sodium chloride solution, anddried over anhydrous magnesium sulfate. The solvent was removed underreduced pressure to give 1.32 g of a crude product. The crude productwas purified by silica gel column chromatography. Eluates obtained withn-hexane/ethyl acetate (19/1) contained 1.01 g of the compound (21).Yield 77%.

NMR spectal data of the product were as follows: δ_(TMS) ^(CDCl).sbsp.3: ppm; 0.88 (21H), 2.87 (1H, m), 3.7-4.3 (2H, m), 5.43 (2H, m), 9.97(1H, d, J=3 HZ).

EXAMPLE 31 ##STR54##

THF (550 ml) was added to 15.3 g (552 mmoles) of a mineral oildispersion of lithium (content 25%, containing 1% sodium), and under icecooling, 70.3 g (550 mmoles) of naphthalene was added in an atmosphereof nitrogen. Under ice cooling, the mixture was stirred for 2 hours toprepare a dark green anion radical solution. 25.1 g (50 mmoles) ofacetylene aldehyde (21) and 18.7 ml (320 moles) of t-butanol weredissolved in 120 ml of THF, and the solution was cooled to -70° C. Theabove anion radical solution cooled at -70° C. was added. The mixturewas stirred at -70° C. for 15 minutes, and 50 g of ammonium chloride wasadded. Furthermore, ethanol was added until the dark green color ofanion radical disappeared. Saturated aqueous ammonium chloride solution(900 ml) was added, and the mixture was extracted twice with 700 ml ofethyl acetate. The organic layers were combined, washed twice withsaturated aqueous sodium chloride solution, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure.The resulting crude product was purified by silica gel columnchromatography to give 5.34 g (yield 21%) of the compound (21α) ineluates obtained with hexane/ethyl acetate (19/1) and 12.95 g (yield51%) of the compound (21β) in eluates obtained with hexane/ethyl cetate(9/1).

Spectral data of the products were as follows: [21α] NMR (δ_(TMS)^(CDCl).sbsp.3): 0.8-1.0 (21H), 3.86 (1H, q, S=6 Hz), 4.05 (1H, br),4.38 (1H, bt, J=8 Hz), 4.96 (1H, brs), 5.08 (1H, brs), 5.45 (2H, m).

IR (cm⁻¹, liquid film): 3350, 3080, 1662, 1255, 1115, 1002, 968, 935,835, 772.

MS 508 (M⁺), 491 (M-17), 451 (M-57). [21β] NMR (δ_(TMS) ^(CDCl).sbsp.3): 0.8-1.0 (21H), 3.77 (1H, m), 4.05 (1H, br), 4.15 (1H, brs), 4.95 (1H,brs), 5.07 (1H, brs), 5.46 (2H, m).

IR (cm⁻¹, liquid film): 3350, 3080, 1662, 1255, 1115, 1002, 968, 937,835, 772.

MS 508 (M⁺), 491 (M-17), 451 (M-57).

EXAMPLE 32 ##STR55##

Pyridine (about 250 microliters; about 4 equivalents) was added at -20°C. in a stream of nitrogen to a methylene chloride solution (4 ml) of400 mg (0.79 mmole) of(1S,5S,6S,7R)-2-hydroxy-3-methylene-6-[(E,3S)-3-t-butyldimethylsilyloxy-1-octenyl]-7-t-butyldimethylsilyloxybicyclo[3.3.0]octane(21), and then 122 microliters (1.6 mmole) of methyl chloroformate wasadded. The mixture was stirred for 1 hour. Then, it was further stirredfor 30 minutes at 0° C. Water was added to terminate the reaction, andthe reaction mixture was extracted with ethyl acetate. The organic layerwas washed with aqueous potassium hydrogensulfate solution, saturatedaqueous sodium hydrogen carbonate solution and saturated aqueous sodiumchloride solution in this order, and dried over anhydrous magnesiumsulfate. Under reduced pressure, the solvent was evaporated, and theresidue was subjected to silica gel column chromatography (hexane/ethylacetate=15/1) to give 377 mg (85%) of the 2-methylcarbonyldioxy compound(16).

IR (cm⁻¹, neat): 2950, 2860, 1750, 1460, 1440, 1360, 1260, 1120.

NMR (δppm, CDCl₃): 0.85 (s, 9H), 0.87 (s, 9H), 0.8-2.6 (m, 18H), 3.75(m, 1H), 3.8 (s, 3H), 4.07 (m, 1H), 5.0 (s, 1H), 5.15 (s, 1H), 5.3 (s,1H), 5.5 (m, 2H).

EXAMPLE 33

In accordance with Example 31, compounds having different ##STR56##moieties in formula [VI] were syntehsized as shown in the followingtable.

    ______________________________________                                         No.Run                                                                             ##STR57##          Yield NMR(δppm, CDCl.sub.3)                    ______________________________________                                              ##STR58##         Yield (αβ mixture): 75% NMR(δppm,                             CDCl.sub.3); 0.8-1.0(21H, m), 3.5-4.2 (4H, m),                               4.9(1H, brs), 5.1(1H, brs), 5.45(2H, m)               2                                                                                   ##STR59##         Yield (αβ mixture): 70% 0.8-1.0(21H,                               m), 3.5-4.2 (4H, m), 4.9(1H, brs), 5.1(1H, brs),                              5.45(2H, m)                                           3                                                                                   ##STR60##         Yield (αβ mixture): 68% 0.9-1.0(21H,                               m), 3.3-4.2 (4H, m), 4.8(1H, brs), 5.1(1H, brs),                              5.43(2H, m)                                           4                                                                                   ##STR61##         Yield (αβ mixture): 74% 0.9-1.0(21H,                               m), 3.4-4.2 (4H, m), 4.9(1H, brs), 5.1(1H, brs),                              5.45(2H, m)                                           5                                                                                   ##STR62##         Yield (αβ mixture): 63% 0.9-1.0(21H,                               m), 1.13(6H, s), 3.4-4.2(4H, m), 4.9(1H, brs),                                5.1(1H, brs), 5.45(2H, m)                             6                                                                                   ##STR63##         Yield (αβ mixture): 70% 0.9-1.0(12H,                               m), 1.1(3H, s), 3.4-4.1(4H, m), 4.85(1H, brs),                                5.1(1H, brs), 5.45(2H, m)                             7                                                                                   ##STR64##         Yield (αβ mixture): 65% 0.9-1.0(12H,                               m), 3.4-4.2(4H, m), 4.7-5.6(7H,                       ______________________________________                                                                m)                                                

EXAMPLE 34

In accordance with Example 32, compounds having different ##STR65##moieties in formula [IV-b] were synthesized as shown in the followingtable.

    ______________________________________                                         No.Run                                                                             ##STR66##          CDCl.sub.3)Yield NMR (δ ppm,                   ______________________________________                                              ##STR67##         Yield: 90% NMR (δ ppm, CDCl.sub.3);                                     0.8-1.0(21H, m), 3.7-4.1 (2H, m), 3.8(3H, s), 5.0                             1H, s), 5.15(1H, s), 5.3 (1H, s), 5.5(2H, m)          2                                                                                   ##STR68##         Yield: 85% 0.8-1.0(21H, m), 3.6-4.1 (2H, m),                                  3.8(3H, s), 5.0 (1H, s), 5.15(1H, s), 5.3 (1H,                                s), 5.5(2H, m)                                        3                                                                                   ##STR69##         Yield: 87% 0.9-1.0(21H, m), 3.5-4.1 (2H, m),                                  3.75(3H, s), 5.0 (1H, s), 5.2(1H, s), 5.3 (1H,                                s), 5.5(2H, m)                                        4                                                                                   ##STR70##          Yield: 75% 0.9-1.0(21H, m), 3.7-4.1 (2H, m),                                 3.75(3H, s), 5.0 (1H, s), 5.15(1H, s), 5.3 (1H,                               s), 5.5(2H, m)                                        5                                                                                   ##STR71##         Yield: 91% 0.9-1.0(21H, m), 1.13(6H, s),                                      3.6-4.1(2H, m), 3.75(3H, s), 5.0(1H, s), 5.15(1H,                             s), 5.3(1H, s), 5.5(2H, m)                            6                                                                                   ##STR72##         Yield: 87% 0.9-1.0(12H, m), 1.1(3H, s),                                       3.7-4.1(2H, m), 3.8(3H, s), 5.0(1H, s), 5.2(1H,                               s), 5.3(1H, s), 5.5(2H, m)                            7                                                                                   ##STR73##         Yield: 81% 0.9-1.0(12H, m), 3.7-4.1 (2H, m),                                  3.8(3H, s), 4.7-5.6 (7H, m)                           ______________________________________                                    

EXAMPLE 35

In accordance with Example 11, compounds having different ##STR74##moieties in formula [I] were synthesized as shown in the followingtable.

    ______________________________________                                         No.Run                                                                             ##STR75##          Yield   Spectrum                                     ______________________________________                                              ##STR76##         75      as in Example 3                               2                                                                                   ##STR77##         65      as in Example 10                              3                                                                                   ##STR78##         60      as in Example 5                               4                                                                                   ##STR79##         69      as in Example 9                               5                                                                                   ##STR80##         80      as in Example 8                               6                                                                                   ##STR81##         82      as in Example 4                               7                                                                                   ##STR82##         55      as in Example 7                               ______________________________________                                    

EXAMPLE 36 ##STR83##

Anhydrous disodium phosphate (41 mg; 0.29 mmole) was added in a streamof nitrogen to a solution of 62 mg (0.071 mmole) of4,4-bis(phenylsulfonyl)isocarbacyclin methylester-11,15(t-butyldimethylsilyl)ether (2) in 1.5 ml of anhydrousmethanol. The mixture was cooled to -30° C. To the solution was added600 mg of sodium amalgam (6% in Hg), and the mixture was stirred for 2hours. Furthermore, 200 mg of sodium amalgam was added and the mixturewas stirred for 3 hours. The reaction was terminated by adding aqueousammonium chloride solution, and the reaction mixture was extracted withdiethyl ether. The organic layer was washed with saturated aqueoussodium chloride solution, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The crude product was subjected tosilica gel column chromatography (n-hexane/ethyl acetate=50:1→10:1) togive 36 mg (86%) of isocarbacyclin methylester-11,15-bis(t-butyldimethylsilyl)ether. This product agreed in TLCand spectral data with a separately prepared authentic sample.

NMR (δppm, CDCl₃): 0.9 (s+m, 21H), 1.2-2.5 (m, 22H), 3.0 (m, 1H), 3.7(s, 3H), 3.7-4.1 (m, 2H), 5.3 (m, 1H), 5.55 (m, 2H).

TLC:Rf=0.75 (n=hexane:ethyl acetate=4:1).

To a solution of 35 mg (0.06 mmole) of the resulting isocarbacyclinmethyl ester-11,15-bis(t-butyldimethylsilyl)ether in 3 ml of dry THF wasadded 400 microliters (0.4 mmole) of tetrabutyl ammonium fluoride (1M inTHF) at 0° C. Thirty minutes later, the temperature of the mixture wasraised to room temperature, and it was stirred at room temperature for14 hours. Water was added to terminate the reaction. The reactionmixture was extracted with ethyl acetate. The organic layer was washedwith saturated aqueous sodium chloride solution, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure to remove thesolvent. The crude product was subjected to silica gel columnchromatography (n-hexane/ethyl acetate=1:1→1:2) to give 18 mg (85%) ofisocarbacyclin methyl ester (23). This produce agreed in HPLC, TLC andspectral data with a separately synthesized authentic sample.

NMR (δppm, CDCl₃): 0.9 (m, 3H), 1.2-2.5 (m, 24H), 3.0 (m, 1H), 3.7 (s,3H), 3.7-4.1 (m, 2H), 5.3 (m, 1H), 5.55 (m, 2H).

TLC:Rf=0.5 (n=hexane:ethyl acetate=1:4).

HPLC: (Zorbax-SIL 2.5% ethanol hexane 1.3 ml/min.)

EXAMPLE 37 ##STR84##

Anhydrous disodium phosphate (228 mg; 0.2 mmole) was added to a solutionof 45 mg (0.05 mmole) of 17(S),20-dimethyl-4,4-bis(phenylsulfonyl)isocarbacyclin methylester-11,15-bis(t-butyldimethylsilyl)ether (5) in 1.5 ml of anhydrousmethanol, and the mixture was cooled to -30° C. Sodium agalgam (6% inHg; 600 mg) was added, and the mixture was stirred for 6 hours.

The reaction was terminated by adding aqueous ammonium chloridesolution, and the reaction mixture was extracted with diethyl ether. Theorganic layer was washed with saturated aqueous sodium chloridesolution, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure. The crude product was subjected tosilica gel column chromatography (n-hexane:ethyl acetate=50:1→10:1) togive 24 mg (79%) of 17(S), 20-dimethylisocarbacyclin methylester-11,15-bis(t-butyldimethylsilyl)ether (24). This product agreed inLC and spectral data with a separately synthesized authentic sample.

NMR (δppm, CDCl₃): 0.9 (s+m, 21H), 1.0-2.5 (m, 26H), 3.0 (m, 1H), 3.7(s, 3H), 3.7-4.1 (m, 2H), 5.3 (m, 1H), 5.55 (m, 2H).

TLC:Rf=0.75 (n=hexane:ethyl acetate=4:1).

EXAMPLE 38 ##STR85##

Anhydrous disodium phosphate (24 mg; 0.17 mmole) was added in a streamof nitrogen to a solution of 34 mg (0.04 mmole) of15-deoxy-16-methyl-16-hydroxy-4,4-bis(phenylsulfonyl)isocarbacyclinmethyl ester-11-t-butyldimethylsilyl ether-16-trimethylsilyl ether (6)in 1 ml of anhydrous methanol, and the mixture was cooled to -30° C.Four hundred milligrams of sodium amalgam (6% in Hg) was added, and themixture was stirred for 7 hours. The reaction was terminated by addingaqueous ammonium chloride solution, and the reaction mixture wasextracted with diethyl ether. The organic layer was washed withsaturated aqueous sodium chloride solution and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure.The crude product was subjected to silica gel column chromatography(n-hexane/ethyl acetate=50:1→10:1) to give 17 mg (75%) of15-deoxy-16-methyl-16-hydroxyisocarbacyclin methylester-11-t-butyldimethylsilyl ether-16-trimethylsilyl ether. Thisproduct agreed in TLC and spectra data with an authentic sampleseparated synthesized.

NMR (δppm, CDCl₃): 0.9 (s+m, 12H), 1.1 (s, 3H), 1.2-2.5 (m, 22H), 3.0(m, 1H), 3.65 (s, 3H), 3.8-4.0 (m, 1H), 5.3 (m, 1H), 5.55 (m, 2H).

TLC:Rf=0.75 (n=hexane:ethyl acetate=4:1).

EXAMPLE 39 ##STR86##

Anhydrous disotium phosphate (36 mg; 0.25 mmole) was added in a streamof nitrogen to a solution of 51 mg (0.059 mmole) of16,17,18,19,20-pentanor-15-cyclopentyl-4,4-bis(phenylsulfonyl)isocarbacyclinmethyl ester-11,15-bis(t-butyldimethylsilyl)ether (9), and the mixturewas cooled to -30° C. Six hundred milligrams of sodium amalgam (6% inHg) was added, and the mixture was stirred for 5 hours. The reaction wasterminated by adding aqueous ammonium chloride solution. The reactionmixture was extracted with diethyl ether, and the organic layer waswashed with saturated aqueous sodium chloride solution, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure. The crude product was subjected to silica gel columnchromatography (n-hexane/ethyl acetate=50:1→10:1) to give 25 mg (75%) of16,17,18,19,20-pentanor-15-cyclopentylisocarbacyclin methylester-11,15-bis(t-butyldimethylsilyl)ether. This product agreed in TLCand spectral data with a separately synthesized authentic sample.

NMR (δppm, CDCl₃): 0.9 (s, 18H), 1.0-2.5 (m, 23H), 3.0 (m, 1H), 3.7 (s,3H), 3.7-4.1 (m, 2H), 5.3 (m, 1H), 5.55 (m, 2H).

TLC:Rf=0.75 (n=hexane:ethyl acetate=4:1).

EXAMPLE 40

The disilyl compounds obtained in Examples 37 to 39 were deprotected asin Example 36.

The NMR spectra of the deprotected products are shown below. ##STR87##

(δppm, CDCl₃): 0.9 (m, 3H), 1.0-2.5 (m, 28H), 0.3 (m, 1H), 3.7 (s, 3H),3.0-4.1 (m, 2H), 5.3 (m, 1H), 5.55 (m, 2H). ##STR88##

0.9 (m, 3H), 1.1 (s, 3H), 1.2-2.5 (m, 24H), 3.0 (m, 1H), 3.65 (s, 3H),3.8-4.0 (m, 1H), 5.3 (m, 1H), 5.55 (m, 1H). ##STR89##

1.0-2.5 (m, 25H), 3.0 (m, 1H), 3.7 (s, 3H), 3.7-4.1 (m, 2H), 5.3 (m,1H), 5.55 (m, 1H).

EXAMPLE 41 ##STR90##

Dry methanol (90 ml) was added to 3.31 g (0.14 gram-atom) of magnesiummetal, and the mixture was stirred at room temperature in an atmosphereof nitrogen. Then, a solution of 11.9 g (13.6 mmole) of the bissulfonylcompound (2) in 180 ml of dry methanol was added. The mixture wasstirred while being warmed over an oil bath. When the solvent began toreflux, the oil bath was removed, and the mixture was stirred for 30minutes while spontaneously refluxing the solvent at room temperature.Saturated aqueous ammonium chloride solution (450 ml) was added, and thereaction mixture was extracted twice with 600 ml of ethyl acetate. Theorganic layers were combined, washed with 300 ml of saturated aqueouspotassium hydrogensulfate solution, 300 ml of saturated aqueous sodiumbicarbonate solution and 300 ml of saturated aqueous sodium chloridesolution, and dried over anhydrous magnesium sulfate. The solvent wasevaporated, and the resulting crude product (8.23 g) was purified bysilica gel column chromatography to give 6.52 g (yield 81%) of thedesulfonylated compound (27) in eluates obtained with 7:1 hexane-ethylacetate).

NMR (δ_(TMS) ^(CDCl).sbsp.3): 0.8-1.0 (21H), 2.88 (1H, m), 3.67 (3H, s),3.74 (1H, m), 4.06 (1H, br), 5.25 (1H, brs), 5.48 (2H, m).

EXAMPLE 42-a

(2R,3R,4R)-4-t-butyldimethylsilyloxy-3-[(E,3S)-3-t-butyldimethylsilyloxy-1-octenyl]-2-(3-trimethylsilyl-2-propynyl)cyclopentanone:##STR91##

t-Butyllithium (1.7M, 194 ml, 330 mmoles) was put in a 2-literthree-necked flask purged with argon, and cooled to -78° C. Separately,60.58 g (165 mmoles) of (E,3S)-3-t-butyldimethylsilyloxy-1-iodo-1-octene was taken into a 200 ml of aneggplant-shaped flask, cooled to -78° C., and dried under reducedpressure. The eggplant-shaped flask was purged with nitrogen, and 100 mlof dry diethyl ether was put into it, and cooled to -78° C. The ethersolution was then added to the t-butyllithium in the three-necked flaskmentioned above by means of a stainless steel tube under argon pressure.The mixture was stirred at -78° C. for 3 hours. Separately, a 500 mleggplant-shaped flask was charged with 31.43 g (165 mmoles) of cuprousiodide. The inside of the flask was dried under reduced pressure andagain purged with argon. 220 ml of THF and 90.3 ml (363 mmoles) oftributylphosphine were added, and stirred at 25° C. to form a uniformsolution. The uniform solution was cooled to -78° C. The uniformsolution was cooled to -78° C., and then added by means of a stainlesssteel tube under argon pressure to the previously preparedalkenyllithium solution. This solution was also stirred at -78° C. for 1hour. Then, a solution of 31.86 g (150 mmoles) of(R)-4-t-butyldimehylsilyloxy-2-cyclopentenone (28) in 220 ml of THF wasadded at -78° C. over the course of 2 hours by means of a stainlesssteel tube. The reaction solution was heated to -50° C., stirred for 30minutes, and again cooled to -78° C. Then, 144 ml ofhexamethylphosphoric triamide was added, and the mixture was furtherstirred at -78° C. for 30 minutes. A solution of 69.39 g (180 mmoles) oftriphenyltin chloride in 160 ml of THF was added at a time at -78° byusing a stainless steel tube. The mixture was then heated to -30° C.,and 55.53 g (233 mmoles) of 3-iodo-1-trimethylsilyl-1-propyne was added,and the mixture was stirred for 1.5 hours. The reaction mixture waspoured into 700 ml of saturated aqueous ammonium chloride solution.Furthermore, 500 ml of n-hexane was added, and the mixture wasvigorously stirred. The organic layer was washed with saturated aqueoussodium chloride solution and dried over anhydrous magnesium sulfate,followed by filtration and concentration under reduced pressure. To theresulting solution was added 700 ml of n-hexane, and 5 ml portions of35% hydrogen peroxide solution (total 60 ml) were added to oxidizetributylphosphine. The insoluble materials were removed by filtrationthrough Celite. The filtrate was transferred to a separating funnel. Theorganic layer was washed with an equal amount mixture of aqueous ammoniaand a saturated aqueous solution of ammonium chloride to remove thecopper ion. The organic layer was then washed with saturated aqueousammonium chloride solution and saturated aqueous sodium chloridesolution, dried over anhydrous magnesium sulfate, filtered, andconcentrated under reduced pressure to give 127 g of a crude product.The crude product was subjected to silica gel column chromatography(Daiso Gel IR-60, 1800 g; hexane/benzene-1:1) to give 55.0 g (yield 65%)of(2R,3R,4R)-4-t-butyldimethylsilyloxy-3-[(E,3S)-3-t-butyldimetylsilyloxy-10-octenyl]-2-(3-trimethylsilyl-2-propynyl)cyclopentanone(29).

TLC:Rf=0.57 (benzene).

IR (liquid film): cm⁻¹. 2980, 2960, 2880, 2200, 1755, 1720, 1470, 1460.

EI-MS: m/e 564 (M⁺), 507 (M-^(t) Bu)⁺.

¹ H-NMR (CCl₄): δ(ppm) 0.07 (s, 12H, Si(CH₃)₂ ×2), 0.13 (s, 9H,Si(CH₃)₃), 0.89 (s, 18H, SiC(CH₃)₃ ×2), 0.8-1.6 (m, 11H, --(CH₂)₄ CH₃),1.6-3.0 (m, 6H), 3.7-4.2 (m, 2H, CHOSi×2), 5.3-5.6 (m, 2H, --CH═CH--).

EXAMPLE 42-b

(1R,2R,3R)-1-t-butyldimethylsilyloxy-2-[(E,3S)-3-t-butyldimethylsilyloxy-1-octenyl]-4-methylene-3-(3-trimethylsilyl-2-propynyl)cyclopentane:##STR92##

70.0 g (124 mmoles) of(2R,3R,4R)-4-t-butyldimethylsilyloxy-3-[(E,2S)-3-t-butyldimethylsilyloxy-1-octenyl]-2-(3-trimethylsilyl-2-propynyl)cyclopentnone(29) was dissolved in 400 ml of methylene chloride, and a suitableamount of a methylenation agent prepared from zinc, dibromomethane andtitanium tetrachloride in accordance with the method of Lombardo (seeTetrahedron Letters, vol. 23, page 4293, 1982) was added. The mixturewas stirred at room temperature for 10 minutes, and the disappearance ofthe starting material was checked by thin layer chromatography (TLC).The methylenation agent was added several times until the startingmaterial disappeared. After the reaction, the liquid layer of thereaction mixture was taken out by decantation. The remaining solid waswashed twice with methylene chloride, and the washings were taken out bydecantation. To the liquid layer was added n-hexane in a nearly equalamount, and the mixture was transferred to a separating funnel. It waswashed successively with 10% aqueous tartaric acid solution, saturatedaqueous sodium hydrogen carbonate solution and saturated sodium chloridesolution. The organic layer was dried over anhydrous magnesium sulfate,and the solvent was evaporated. There was obtained 66.5 g of a crudeproduct. When the crude product was purified by silica gel columnchromatography, 58.9 g (yield 84%) of(1R,2R,3R)-1-t-butyldimethylsilyloxy-2-[(E,3S)-3-t-butyldimethylsilyloxy-1-octenyl]-4-methylene-3-(3-trimethylsilyl-2-propynyl)cyclopentane(30) from eluates obtained with 1.5% ethyl acetate/n-hexane.

TLC:Rf=0.74 (ethyl acetate/n-hexane=1:19).

IR (liquid film): cm⁻¹ 3090, 2200, 1658, 1460, 1250.

EI-MS: m/e 562 (M⁺), 505 (M-^(t) Bu)⁺.

¹ H-NMR (CDCl₃): δ(ppm) 0.06 (s, 12H, Si(CH₃)₂ ×2), 0.13 (s, 9H),Si(CH₃)₃), 0.89 (s, 18H, SiC(CH₃)₃ ×2), 0.8-1.6 (m, 11H, --CH₂ CH₂ CH₂CH₃), 2.1-3.0 (m, 6H), 3.8-4.25 (m, 2H, CHOSi×2), 5.05 (d, 2H, J=9 Hz,=CH₂), 5.45-5.6 (m, 2H, CH═CH).

EXAMPLE 42-c

(1R,2R,3R,4S)-1-t-butyldimethylsilyloxy-2-[(E,3S)-3-t-butyldimethylsilyloxy-1-octenyl]-4-hydroxymethyl-3-(3-trimethylsilyl-2-propynyl)cyclopentane:##STR93##

The inside of a 2-liter eggplant-shaped flask was purged with nitrogengas, and 11.20 g (91.8 mmoles) of 9-BBN(9-borabicyclo[3.3.1]nonane)dimer was taken into the flask. Freshly distilled THF (170 ml) was addedto form a solution. The reaction solution was cooled with ice, and asolution of 39.70 g (70.6 mmoles) of(1R,2R,3R)-1-t-butyldimethylsilyloxy-2-[(E,3S)-3-t-butyldimethylsilyloxy-1-octenyl]-4-methylene-3-(3-trimethylsilyl-2-propynyl)cyclopentane(30) in 50 ml of THF was added. The mixture was stirred at roomtemperature for 1 hour. The reaction solution was again cooled with ice,and 56 ml of a 5N aqueous solution of sodium hydroxide and then 56 ml of35% hydrogen peroxide solution were added. The reaction mixture wasstirred at 50° C. for 30 minutes, poured into ice water, and extractedtwice with ethyl acetate. The organic layers were washed successivelywith saturated aqueous sodium hydrogen carbonate solution and saturatedaqueous sodium chloride solution, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure. The residuewas purified by silica gel coluimn chromatography to obtain 33.5 g(yield 82%) of(1R,2R,3R,4S)-1-t-butyldimethylsilyloxy-2-[(E,3S)-3-t-butyldimethylsilyloxy-1-octenyl]-4-hydroxymethyl-3-(3-trimethylsilyl-2-propynyl)cyclopentane (31) from eluates obtained with 5% ethylacetate/n-hexane.

TLC:Rf=0.53 (ethyl acetate/n-hexane=1:6).

IR (liquid film): cm⁻¹ 3150-3600, 2200, 1460, 1250.

EI-MS: m/e 581 (M+H)⁺, 580 (M)⁺, 523 (M-^(t) Bu)⁺.

¹ H-NMR δ(CDCl₃): (ppm) 0.04 (s, 12H, Si(CH₃)₂ ×2), 0.13 (s, 9H),Si(CH₃)₃), 0.89(s, 18H, SiC(CH₃)₃ ×2), 0.77-1.65 (m, 11H, --(CH₂)₄ CH₃),2.75-3.05 (br, 1H, --OH), 3.7-3.9 (m, 2H, --CH₂ O--), 3.9-4.12 (m, 2H,CHOSi×2), 5.33-5.53 (m, 2H, --CH═CH--).

EXAMPLE 42-d

(1R,2R,3R,4S)-1-t-butyldimethylsilyloxy-2-[(E,3S)-t-butyldimethylsilyloxy-1-octenyl]-4-hydroxymethyl-3-(2-propynyl)cyclopentane:##STR94##

6.40 g (110 mmoles) of(1R,2R,3R,4S)-1-t-butyldimethylsilyloxy-2-[(E,3S)-3-t-butyldimethylsilyloxy-1-octenyl]-4-hydroxymethyl-3-(3-trimethylsilyl-2-propynyl)cyclopentane(31) was taken into a 1-liter eggplant-shaped flask, and dissolved byadding 500 ml of methanol. Then, 106.3 g of a 28% methanol solution ofsodium methylate was added, and the mixture was stirred at roomtemperature for 30 minutes. Saturated aqueous ammonium chloride solution(300 ml) was added, and the mixture was extracted twice with ethylacetate. The organic layer was successively washed with saturatedaqueous potassium hydrogensulfate solution, saturated aqueous sodiumbicarbonate solution and saturated aqueous sodium chloride solution anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography to obtain 53.9 g (yield 96%) of(1R,2R,3R,4S)-1-t-butyldimethylsilyloxy-2-[(E,3S)-3-t-butyldimethylsilyloxy-1-octenyl]-4-hydroxymethyl-3-(2-propynyl)cyclopentane(32) from eluates obtained with 10% ethyl acetate/n-hexane.

TLC:Rf=0.40 (ethyl acetate/n-hexane=1:6).

IR (liquid film): cm⁻¹ 3600-3100, 3320, 2980, 2950, 2870, 2120, 1460,1430, 1255.

EI-MS: m/e 508 (M)⁺, 451 (M-^(t) Bu)⁺.

¹ H-NMRδ(CDCl₃): (ppm) 0.03 (s, 12H, Si(CH₃)₂ ×2), 0.87 (s, 18H,SiC(CH₃)₃ ×2), 0.8-1.8 (m, 11H, --(CH₂)₄ CH₃), 1.94 (t, 1H, J=3 Hz,--C═C--H), 2.31 (d, 2H, J=3 Hz, --CH₂ 'C═C), 2.0-2.47 (m, 5H), 2.85-3.13(br, 1H, --OH), 3.6-3.9 (m, 2H, --CH₂ O--), 3.9-4.2 (m, 2H, CHOSi×2),5.37-5.52 (m, 2H, --CH═CH--).

EXAMPLE 42-e

(1R,2R,3R,4S)-1-t-butyldimethylsilyloxy-2-[(E,3S)-3-t-butyldimethylsilyloxy-10-octenyl]-4-formyl-3-(2-propynyl)cyclopentane:##STR95##

Oxalyl chloride (5.08 g; 40 mmoles) and 60 ml of dichloromethane weretaken into a nitrogen-purged 500 ml eggplant-shaped flask, and cooled to-50° C. A solution of 6.24 g (80 mmoles) of dimethyl sulfoxide in 20 mlof dichloromethane was added, and the mixture was stirred for 30minutes. A solution of 9.09 g (17.9 mmoles) of(1R,2R,3R,4S)-1-t-butyldimethylsilyloxy-2-[(E,3S)-3-t-butyldimethylsilyloxy-1-octenyl]-4-hydroxymethyl-3-(2-propynyl)cyclopentane(32) in 40 ml of dichloromethane was added, and the mixture was stirredat -50° C. for 30 minutes. Subsequently, 10.1 g (100 mmoles) oftriethylamine was added, and the mixture was stirred at -50° C. for 30minutes. Acetic acid (7.2 g; 120 mmoles) was added, and the mixture wasstirred for 10 minutes. The reaction mixture was poured into saturatedaqueous ammonium chloride solution and extracted with dichloromethane.The organic layer was washed successively with saturated aqueouspotassium hydrogensulfate and saturated aqueous sodium chloridesolution, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure to give 9.05 g (yield of the crudeproduct 100%) of(1R,2R,3R,4S)-1-t-butyldimethylsilyloxy-2-[(E,3S)-3-t-butyldimethylsilyloxy-1-octenyl]-4-formyl-3-(2-propynyl)cyclopentane(20).

TLC:Rf=0.65 (n-hexane:ethyl acetate=4:1).

¹ H-NMRδ(CDCl₃): (ppm) 0.07 (s, 12H, Si(CH₃)₂ ×2), 0.87 (s, 18H,SiC(CH₃)₃ ×2), 0.7-1.8 (m, 11H, --(CH₂)₄ CH₃), 1.8-2.4 (m, 7H), 2.65-3.1(m, 1H, --CHCO--), 3.6-4.2 (m, 2H, --CHOSi×2), 5.2-5.45 (m, 2H,--CH═CH--), 9.75 (d, 1H, J=3 Hz, --CHO).

EXAMPLE 43-a ##STR96##

An argon-purged 150 ml reaction tube was charged with 593.1 mg(1.61×10⁻³ mole) of (E)-1-iodo-3-t-butylsilyloxy-1-octene and 6 ml ofdry diethyl ether, and the mixture was stirred at -95° C. Then, 1.72 ml(3.22×10⁻³ mole) of t-butyllithium (1.87M pentane) was added viasyringe, and the mixture was stirred at -95° to -78° C. for 3 hours.Separately, 306.6 mg (1.61×10⁻³ mole) of cuprous iodide was taken into a30 ml eggplant-shaped flask, and the inside of the flask was dried byheating under reduced pressure and then purged with argon. Dry THF (6ml) and 1.04 ml (4.19×10⁻³ mole) of tributylphosphine were introducedinto the flask and the entire mixture was stirred at 23° C. to form auniform solution. The solution was cooled to -78° C. and added at a timeunder argon pressure to the vinyllithium solution prepared previously.Furtehrmore, 6 ml of dry THF was added by washing the flask with it. Themixture was stirred at -78° C. for 10 minutes, a solution of 325.6 mg(153×10⁻³ mole) of 4-t-butyldimethylsiloxy-2-cyclopentenone in 12 ml ofTHF was added dropwise over 1 hour. The flask was washed with 1 ml ofTHF, and the mixture was stirred for 10 minutes. HMPA (1.5 ml) wasadded, and the mixture was stirred for 30 minutes. Then, a THF solution(2 ml) of 627.6 mg (1.61×10⁻³ mole) of triphenyltin chloride was added.The mixture was heated to -30° C., and an HMPA solution of 814.2 mg(3.06×10⁻³ mole) of 1-iodo-6-carbomethoxy-2-hexyne was added, and themixture was stirred at -30° C. for 4.5 hours. The reaction mixture wassubsequently left to stand at -27° C. for 13 hours, and 20 ml ofsaturated aqueous ammonium chloride solution was added. The mixture wasvigorously shaken and separated into an organic layer and an aqueouslayer. The aqueous layer was extracted twice with 20 ml of diethylether. The ether layers were combined, washed with saturated aqueoussodium chloride solution, and dried over anhydrous sodium sulfate. Thedried solution was filtered, concentrated under reduced pressure andsubjected to silica gel column chromatography (Merck 7734, 50 g;1:60=ethyl acetate:hexane, 600 ml→1:20=ethyl acetate:hexane, 200 ml) togive 542.1 mg (yield 59.7%) of11,15-bis(t-butyldimethylsilyl)-5,6-dehydroprostaglandin E₂ methyl ester(33).

TLC:Rf=0.50 (ethyl acetate/hexane=1:5).

IR (liquid film): 1746, 1246, 827, 767 cm⁻¹.

¹ H NMR (CDCl₃ -CCl₄ =1:1)δ: 0.04 and 0.06 (each s, 12, SiCH₃ ×2), 0.89(s, 18, SiC(CH₃)₃ ×2), 0.92 (t, 1, J=6.5 Hz, CH₃), 1.1-1.5 (m, 8, CH₂×4), 1.7-2.9 (m, 12, CH₂ CO×2, CH₂ C.tbd.×2, CH×2 and CH₂), 3.65 (s, 3,OCH₃), 4.05 (m, 2, CHOSi×2), 5.4-5.7 (m, 2, vinyl).

¹³ C NMR (CDCl₃)δ: -4.7, -4.5, -4.2, 13.6, 14.0, 16.9, 18.0, 18.2, 22.6,24.2, 25.0, 25.8, 25.9, 31.9, 32.7, 38.6, 47.7, 51.4, 51.9, 52.9, 72.7,73.1, 77.3, 80.8, 128.2, 136.8, 173.4, 213.4.

[α]_(D) ²¹ ; -13.9° (C 1.59, CH₃ OH).

EXAMPLE 43-b ##STR97##

An aliquot (1.33 g; 2.25 mmoles) of11,15-bis(t-butyldimethylsilyl)-5,6-dehydroprostaglandin E₂ methyl ester(33) obtained in Example 43-a was dissolved in 30 ml of methylenechloride. Under ice cooling, a suitable amount of a methylenation agentprepared in accordance with the method of Lombardo et al. from zinc,dibromomethane and titanium tetrachloride (see Tetrahedron Letters, vol.23, page 4293, 1982) was added. With stirring at room temperature, thedisappearance of the starting material was checked by thin layerchromatography (TLC) and the end point of the reaction was determined.(The total reaction time was 45 minutes.) The reaction mixture was addedto 150 ml of saturated aqueous sodium bicarbonate solution, filteredthrough Celite, and extracted twice with n-hexane. The organic layerswere combined, washed with saturated aqueous sodium chloride solution,and dried over anhydrous magnesium sulfate. The solvent was evaporatedto give 1.2 g of a residue. The residue was purified by silica gelchromatography to obtain 928 mg (yield 70%) of11,15-bis(t-butyldimethylsilyl)-5,6-dehydro-9-deoxy-9-methyleneprostaglandin E₂ methyl ester (34) from eluates obtained with2% ethyl acetate/n-hexane.

NMR (δppm, CDCl₃): 0.75-1.0 (21H), 3.67 (3H, s), 3.6-4.3 (2H, m),4.8-5.2 (2H, br), 5.3-5.7 (2H, m).

IR (cm⁻¹, neat): 2960, 2940, 2860, 1740, 1458, 1428, 1250, 1112, 1000,965, 835, 773.

EXAMPLE 43-c ##STR98##

The compound (34) (416 mg) was dissolved in 15 ml of dry THF, and thesolution was cooled to 0° C. A 0.5M hexane solution of9-BBN(9-borabicyclo[3.3.1]nonane) (5.64 mg) was added dropwise, and themixture was stirred at 0° C. for 2.5 hours. 3N--NaOH (1.2 ml) and then1.0 ml of 30% H₂ O₂ were added. The mixture was stirred at 0° C. for 10minutes and at 25° C. for 30 minutes. A saturated aqueous solution ofsodium sulfate was added to the reaction mixture, and the mixture wasextracted three times with 20 ml of diethyl ether. The organic layerswere treated in a customary manner to form a crude product. The crudeproduct was subjected to silica gel column chromatography (40 g ofsilica gel; hexane:ethyl acetate=7:1) to give 327 mg (yield 76%) of theproduct (35).

TLC:Rf=0.46 (hexane/ethyl acetate=2:1).

IR (CHCl₃ solution, cm⁻¹): 3400, 2840, 1760, 1360, 820.

¹ H NMR (CDCl₃ 90 MHZ, ppm)δ: 0.40-0.10 (s, 12, Si CH₃ ×4), 0.70-1.40(s, 21, SiC(CH₃)₃ ×2&CH₃), 1.10-2.58 (m, 19, CH₂ ×9, OH), 3.70 (s, 3,OCH₃).

EXAMPLE 43-d ##STR99##

Seven mg of PDC (pyridinium dichromate) was added at room temperature to46 mg of the compound (35) dissolved in 10 ml of dichloromethane, andthe mixture was stirred for 11 hours. The insoluble materials wereremoved from the reaction mixture by filtration, and the filtrate wasconcentrated to give a crude product. The crude product was purified bycolumn chromatography (silica gel 5 g; hexane:ethyl acetate=10:1) togive 38 mg (yield 85%) of the product (36).

TLC:Rf=0.59 (n-hexane/ethyl acetate=2/1).

¹ H NMR (CDCl₃ 90 MHZ, ppm)δ: 0.02-0.10 (s, 12, SiCH₃ ×4), 0.66-1.01 (s,21, SiC(CH₃)₃ ×2&CH₃), 1.01-2.64 (m, 21, CH₂ ×9, &CH×3), 3.64 (s, 3,OCH₃), 3.74-4.18 (m, 2, SiOCH×2), 5.28-5.50 (m, 2, vinyl), 9.95 (d,J=2.93 Hz, 1, CHO).

EXAMPLE 43-e ##STR100##

(A) A 0.28M diethyl ether solution (0.15 ml) of bis(dimethylphenylsilyl)copper lithium was slowly added at -78° C. to 1.5 ml of a THF solutionof 19.4 mg of the aldehyde (36), and the mixture was stirred for 20minutes. Carbon disulfide (0.004 ml) was added at this temperature, and5 minutes later, 0.06 ml of HMPA was added. The mixture was furtherstirred for 30 minutes. Methyl iodide (0.004 ml) was added, and themixture was stirred for 40 minutes. To the reaction mixture was added1.5 ml of saturated aqueous ammonium chloride solution, and the mixturewas extracted with diethyl ether. The ether extract was worked up in acustomary manner to give a crude product. The crude product was purifiedby column chromatography (silica gel 5 g; hexane:ethyl acetate=20:1) togive 4.8 mg (yield 18%) of the product (37) and further 6.1 mg (yield28%) of the alcohol compound in which the ##STR101## was changed to ahydrogen atom. This alcohol compound could be converted to the desiredproduct (37) (yield 22%) by treating it with n-butyllithium and then onHMPA, CS₂ and CH₃.

Spectral data of comound (37) were as follows:

¹ H NMR (270 MHz, CDCl₃)δ: 0.1-0.1 (m, 12, OSiCH₃ ×4), 0.40, 0.44 (s,each, 6, SiCH₃ ×2), 0.7-1.0 (m, 21, OSiC(CH₃)₃ ×2, CH₃), 1.0-2.6 (m, 21,CH₂ ×9, CH×3), 2.50 (S, 3, SCH₃), 3.68 (s, 3, OCH₃), 3.6-3.8 (m, 1,C(15)H), 3.9-4.1 (m, 1, C(11)H), 5.20 (dd, 1, J=15.5, 7.7 Hz, C(13)H),5.37 (dd, 1, J=15.5, 5.6 Hz, C(14)H), 6.38 (d, 1, J=2.3 Hz, CH(Si)O),7.3-7.6 (m, 5, aromatic).

(B) Thirty mg of the aldehyde (36) was reacted in 2 ml of THF withbis(dimethylphenylsilyl)copper lithium prepared from 18.8 mg of coppercyanide and 0.75 ml of dimethylphenylsilyl lithium (0.56M). Twentyminutes later, the reaction mixture was treated with saturated aqueousammonium chloride solution and extracted with diethyl ether. The extractwas worked up in a customary manner. The crude product was purified bysilica gel column chromatography to give 26.8 mg (yield 73.6%) of thealcohol compound.

The spectral data of the alcohol compound were as follows:

¹ H NMR (270 MHz, CDCl₃, δ): 0.015, 0.01, 0.03 (s, each, 12, OSiCH₃ ×2),0.36, 0.37 (s, each, 6 SiCH₃ ×2), 0.7-1.0 (m, 21, SiC(CH₃)₃ ×2, CH₃),1.1-2.5 (m, 22, CH₂ ×9, CH×3, OH), 3.67 (s, 3, OCH₃), 3.8-4.1 (m, 3,CHO×2, CH(Si)O), 5.2-5.5 (m, 2, vinyl), 7.3-7.6 (m, 5, aromatic).

The resulting alcohol compound was treated in 2.6 ml of THF with 0.026ml of n-butyllithium (1.36M hexane solution), 0.08 ml of carbondisulfide, 0.08 ml of methyl iodide and 0.08 ml of HMPA at -78° C. Thereaction mixture was worked up in a customary manner to give 16.6 mg(yield 57%) of the desired product (37).

EXAMPLES 43-f ##STR102##

(A) Two milligrams of the compound (37) was treated in 0.5 ml of benzenewith 20 mg of tri-n-butyltin hydride and 15 mg of (t-BuO)₂ at 65° C. for15 hours and then at 80° C. for 20 hours. The resulting crude productwas purified by column chromatography (silica gel 4 g; hexane:ethylacetate=50:1, 20:1) to give 0.7 mg (yield about 30%) of the desiredproduct (38).

The spectral data of the compound (38) were as follows:

¹ H NMR (270 MHz, CDCl₃)δ: 0.1-0.1 (m, 12, OSi CH₃ ×4), 0.2-0.3 (m, 6,SiCH₃ ×2), 0.8-1.0 (m, 21, SiC(CH₃)₃ ×2, CH₃), 1.0-2.7 (m, 22, CH₂ ×9,CH×4), 3.65, 3.67 (s, each, 3, OCH₃), 3.9-4.1 (m, 2, CH×2), 4.9-5.0,5.0-5.1 (m, 1, C(5)H), 5.3-5.5 (m, 2, C(13)H, C(14)H), 7.2-7.5 (m, 5,aromatic).

(B) The compound (37) (11 mg) was treated in 10 ml of toluene with 0.16ml of tri-n-butyltin hydride and 60 mg of (t-BuO)₂ at 80° C. for 17hours, and then purified by column chromatography to give 9 mg (yield94%) of the desired product (38).

EXAMPLE 43-g ##STR103##

Trifluoroacetic acid (10 mg) was added to a solution of 0.7 mg of thecompund (38) in 0.5 ml of dry dichlorometane, and the mixture wasstirred at 20° C. for 20 minutes. The reaction mixture was neutralizedwith aqueous sodium bicarbonate solution and extracted with diethylether. The extract was worked up in a customary manner to give 0.6 mg(yield about 80%) of a crude produce (27). Without isolation of the thecompound (27), the crude product was used in the subsequentdesilylation.

EXAMPLE 43-h ##STR104##

Purified isocarbvacyclin methyl ester bis-11,15-t-butyldimethylsilylether (27) (0.6 mg) was dissolved in 0.5 ml of THF, and 50 microlitersof tetra-n-butyl ammonium fluoride (0.5M THF solution) was added, andthe mixture was stirred at room temperature for 12 hours. The reactionmixture was mixed with 3 ml of saturated aqueous sodium chloridesolution, and extracted three times with 5 ml of diethyl ether. Theether layers were worked up in a customary manner to give a crudeproduct. The crude product was purified by column chromatography (silicagel 1 g; hexane:ethyl acetate=3:2→1:1) to give 0.3 mg (yield 90%) of theproduct (23) having the following spectral data.

¹ H NMR (270 MHz, CDCl₃)δ: 0.7-0.1 (m 3, CH₃), 1.0-1.8 (m, 15, CH₂ ×6,CH, OH×2), 1.8-2.2 (m, 15, CH₂ C(0), C(7)H₂ C(12)H), 2.2-2.5 (m, 4,C(5)H₂ C(10)H₂), 2.9-3.1 (m, 1, C(9)H), 3.67 (s, 3, OCH₃), 3.7-3.9 (m,1, C(15)H), 4.0-4.2 (m, 1, C(11)H), 5.30 (br, s, 1 olefin in ring),5.4-5.7 (m, 2, olefin in chain).

EXAMPLE 43-i

In the same way as in Example 43-g, 9.0 mg of the compound (38) wasstirred with 120 microlieters of a 50% dichloromethane solution oftrifluoroacetic acid at 30° C. for 90 minutes. The reaction was treatedin a customary manner to form a crude product. The crude product wasdissolved in 1 ml of THF and reacted with 0. ml of n-Bu₄ NF (10.5M THFsolution) at room temperature for 8 hours. After the reaction, thereaction mixture was worked up as in Example 43-h to give 2.7 mg (yield62%) of the desired product (23).

EXAMPLE 44 ##STR105##

THF (5 ml) was added to 100 mg (3.6 mmoles) of a mineral oil dispersionof lithium (content 25%; containing 1% of sodium), and 500 mg (3.9mmoles) of naphthalene was added. The mixture was stirred for 2 hoursunder ice cooling to prepare an anion radical solution. The solution wascooled to -78° C., and a solution of 44 mg (74 micromoles) of11,15-bis(t-butyldimethylsilyl)-1-nor-1-(1-hydroxyethyl)-5,6-dehydro-9-deoxy-9-formylprostaglandinE₂ and 130 microlieters of t-butyl alcohol. The mixture was stirred for5 minutes, and aqueous ammonium chloride solution was added. The mixturewas extracted three times with 50 ml of ethyl acetate. The organiclayers were washed with aqueous sodium chloride solution, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure togive a crude product. The crude product was purified by silica gelcolumn chromatography to give 23 mg (39 micromoles; yield 53%) of11,15-bis(t-butyldimethylsilyl)-1-nor-1-(1-hydroxsyethyl)-9-hydroxycarbacyclin(40).

TLC:Rf=0.32 (n-hexane:ethyl acetate=1:1).

NMR (CDCl₃, ppm)δ: 0.03 (12H, s), 0.7-1.0 (21H), 1.0-2.4 (24H, m),3.3-4.5 (6H, m), 5.3-5.6 (3H, m).

IR (liquid film): 3380, 3080, 1260, 835, 775, 740 cm⁻¹.

FD-MS: 595 (M+1), 594 (M⁺), 577 (M-17), 537 (M-57).

EI-MS: 576 (M-18, 8), 519 (34), 505 (10), 462 (4), 445 (16), 427 (9),405 (31), 387 (22), 373 (16), 313 (56), 295 (39), 241 (30), 215 (88),199 (40), 163 (73), 147 (100), 131 (54), 105 (69).

What is claimed is:
 1. A novel isocarbacyclin which is a compoundrepresented by the following formula [I] ##STR106## wherein R¹represents a hydrogen atom, or a C₁ -C₄ alkyl or alkenyl group; R² andR³ are identical or different and each represents a hydrogen atom, atri(C₁ -C₇)hydrocarbon-silyl group or a group forming an acetal linkagetogether with the oxygen atom of the hydroxyl group; R⁴ represents ahydrogen atom, a methyl group or a vinyl group; R⁵ represents anunsubstituted linear or branched C₃ -C₈ alkyl group which may beinterrupted by an oxygen atom, a substituted linear or branched C₁ -C₅alkyl group in which the substituent is a C₁ -C₆ alkoxy group or aphenyl, phenoxy or C₃ -C₁₀ cycloalkyl group which may be substitutedfurther, a phenyl group which may be substituted, a phenoxy group whichmay be substituted, or a C₃ -C₁₀ cycloalkyl group which may besubstituted; n is 0 or 1; and Ar represents a substituted orunsubstituted phenyl group, its enantiomorph, or a mixture both in anarbitrary ratio.
 2. The isocarbacyclin of claim 1 wherein R¹ representsa hydrogen atom, a methyl group or an allyl group.
 3. The isocarbacyclinof claim 1 wherein R² and R³ are identical or different, and eachrepresents a hydrogen atom, a trimethylsilyl group, adimethyl-t-butylsilyl group, a tetrahydropyranyl group or amethoxymethyl group.
 4. The isocarbacyclin of claim 1 wherein R⁴represents a hydrogen atom.
 5. The isocarbacyclin of claim 1 wherein R⁵represents a butyl, pentyl, hexyl, heptyl, 2-hexyl, 2-methyl-2-hexyl,2-methylbutyl, 2-methylpentyl, cyclopentyl, cyclohexyl, phenyl, phenoxy,cyclopentylmethyl or cyclohexylmethyl group.
 6. The isocarbacyclin ofclaim 1 wherein n is
 0. 7. The isocarbacyclin of claim 1 wherein Ar is aphenyl or p-tolyl group.